Novel small molecule potentiators of metabotropic glutamate receptors i

ABSTRACT

The present invention relates to small molecule potentiators of metabotropic receptors, in particular of the mGlu2 receptor. The present invention also relates to the use of these compounds for the prevention or treatment of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The present invention thus provides compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein X 2  is N or C—R 2 , X 3  is N or C—R 3 , X 4  is N or C—R 4  provided that none or one of X 2 , X 3  or X 4  is N; Y 1  is N, C or C—R 5 , Y 2  is N, C or C—R 6 , Y 3  is N, C or C—R 7 , Y 4  is N, C or C—R 8  provided that only the moiety Y 1 , Y 2 , Y 3  or Y 4  to which Z is bound is C and further provided at most one of Y 1 , Y 2 , Y 3  or Y 4  is N; Z is O, S, S(O), S(O) 2  or NR Z ; Q is CH 2  or CH 2 CH 2 , where one or two of the hydrogen atoms in CH 2  or CH 2 CH 2  may be replaced by halogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; R 1  is inter alia hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 8 -cycloalkyl, a radical NR 1a R 1b , C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH 2 , aryloxy, hetaryl, hetaryloxy or hetaryl-CH 2 , wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R 1c ; R 2 , R 3  and R 4  are, inter alia, selected from hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, phenyl, C 1 -C 4 -haloalkoxy, a radical (CH 2 ) n NR′R″; R 5 , R 6 , R 7 , R 8  are, independently of each other, selected from hydrogen, halogen, etc.; R a  is C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkyl, which is unsubstituted or carries one radical selected from C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and a radical NR a1 R a2 , R b  is hydrogen, halogen or C 1 -C 4 -alkyl; and the N-oxides and the pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This is the non-provisional of U.S. Provisional Patent Application No.61/318,868, filed on Mar. 30, 2010, the contents of which are herebyincorporated by reference.

The present invention relates to small molecule potentiators ofmetabotropic receptors, in particular of the mGlu2 receptor. The presentinvention also relates to the use of these compounds for the preventionor treatment of neurological and psychiatric disorders associated withglutamate dysfunction and diseases in which metabotropic glutamatereceptors are involved.

BACKGROUND OF THE INVENTION

Glutamate, the major excitatory neurotransmitter in the brain, elicitsits effects by activating ligand-gated cation channels, termedionotropic glutamate receptors (iGluRs), as well as metabotropicglutamate receptors (mGlu receptors). The latter belong to the G-Proteincoupled receptor (GPCR) family 3 (Conn and Pin, Annu. Rev. Pharmacol.Toxicol. 37, 205-37, 1997) and are coupled through heterotrimericG-proteins to intracellular effector systems. These receptor types exertmultiple modulatory effects within the central nervous system (CNS).Eight mGlu receptor subtypes have been cloned from mammalian brain todate. Depending on their G-protein coupling profile, pharmacology andsequence identity, these receptors are classified into three groups(Conn and Pin, Annu. Rev. Pharmacol. Toxicol. 37, 205-37, 1997). Group ImGlu receptors primarily couple through Gq to increases inphosphoinositide hydrolysis and the cellular Ca²⁺-system viaphospholipase C (PLC), and include the mGlu1 receptor and mGlu5receptor. Group II mGlu receptors, which include mGlu2 and mGlu3,inhibit adenylylcyclase (AC), just as group III mGlu receptors, whichcomprise mGlu4, mGlu6, mGlu7 and mGlu8. Thereby, in groups II and III,the pertussis-toxin sensitive G-protein Gi is involved in signaltransduction. However, group II and group III mGlu receptors differ intheir sequence identity and pharmacological profile.

Of the 8 mGlu receptor subtypes various splice variants exist. Withingroup I mGlu receptors the splicing variability is most pronounced. MGlu1 exists in 6 different splicing forms. The receptors mGlu1a/a, 1b/b,1c, 1d and 1f all differ in their C-terminal, intracellular domain(Prezeau et al., Mol. Pharmacol. 49, 422-429, 1996; Soloviev et al.,Biochimica et Biophysica Acta 1446, 161-166, 1999), and mGlu1e istruncated N-terminally, lacking most of the protein coding region (Pinand Duvoisin, Neuropharmacol. 34, 1-26, 1995). So far of mGlu5 (groupI), and the group III receptors mGlu4, mGlu7 and mGlu8 two splicingvariants have been demonstrated. mGlu6 which is located solely inON-bipolar cells of the retina (Nakanishi et al., Brain Res. Rev. 26,230-235, 1998), only has one isoform. The same holds for mGlu2 and mGlu3receptors (Fagni et al., TINS 23 (2), 80-88, 2000).

The synaptic localization of group I mGlu receptors and group II/IIImGlu receptors differs. While group I receptors are locatedpredominantly postsynaptically, group III mGlu receptors rather show apresynaptic localization (Shigemoto et al., J. Neurosci. 17, 7503-7522,1997; Cartmell & Schoepp, J. Neurochem. 75(3), 889-907, 2000). Group IIreceptors seem to be located pre- and postsynaptically, depending onbrain region and synapse-type. A perisynaptic localization of mGlu2 hasalso been demonstrated. In this case, the receptor might only beactivated under high frequency stimulation, then preventing furthertransmitter release and thus reducing pathologically high levels ofglutamate within the synaptic cleft. Autoreceptor function (medialperforant path, mossy fiber-CA3, spinal cord synapse, corticostriatalsynapse) and heteroreceptor functions have been demonstrated for groupII mGlu receptors at synapses in diverse brain regions. The pre- andperisynaptic localization of group II mGlu receptors, combined withtheir auto- and heteroreceptor function and their coupling to inhibitoryintracellular signalling cascades implies an important role of thisreceptor type for the regulation of excitatory neurotransmission.

The first compounds which discriminated between the 3 different groupsof mGlu receptors were low affinity agonists: 3,5-dihydroxyphenylglycine(3,4-DHPG), which selectively stimulates the group 1 mGlu receptors;(2R,4R)-4-aminopyrrolidine-carboxylic acid (2R,4R-APDC) activating groupII mGlu receptors (Monn et al., J. Med. Chem. 39(15), 2990-3000, 1996)and L-Amino-4-phosphonobutyrate (L-AP4, Trombley and Westbrook, J.Neurosci. 12(6), 2043-50, 1992) for the activation of group III mGlureceptors. All these compounds have been valuable tools for theinvestigation of the various functions of mGlu receptors by in vitrostudies, but none of these compounds has been shown to exert potentcentral effects after systemic administration. Other early compounds,which have mainly been used for in vitro studies, turned out to activateionotropic glutamate receptors as well. For the widely used group IImGlu receptor agonist (2S,1′R,2′R,3′R)-2-(2′,3′-dicarboxypropyl)glycinealso activates NMDA receptors.

For studying the in vivo effects and therapeutic applications of groupII agonists, the breakthrough came from the discovery of LY354740 andLY379268 (Formulae given e.g. in D. A. Barda et al., Bioorganic andMedicinal Chemistry Letters, 14, 3099-3102, 2004). These two compoundsare highly specific group II receptor agonists with only very lowaffinity to other mGlu receptors or ionotropic glutamate receptors. Theyhave EC₅₀ values of 10 and 20 nM (LY354740) and 3 and 5 nM (LY379268),for mGlu2 and 3 respectively. While a differentiation between the twogroup II receptors is not possible, a specificity of >1:30.000 towardsgroup I receptors and between 1:100 (mGlu6) to >1:30.000 (mGlu7) togroup III receptors offers a high discrimination potential to thesereceptor types (Cartmell and Schoepp, J. Neurochem. 75(3), 889-907,2000; Bräuner-Osborne et al., J. Med. Chem. 43 (14), 2609-2645, 2000).Both compounds were designed as conformationally constrained analoguesof glutamate (Monn et al., J. Med. Chem. 40(4), 528-37, 1997; J. Med.Chem. 42(6), 1027-40, 1999), and represent competitive agonists at theglutamate binding site. Furthermore these two compounds are systemicallyactive.

Derivatives of these compounds, MGS 0008 and MGS 0028 (Nakazato et al.,J. Med. Chem. 43(25), 4893-909, 2000) and have a higher oralavailability. They also show increased antagonistic effects onPCP-induced head-weaving and hyperactivity in rats. Recently also ahighly selective antagonist for group II mGlu receptors has beenidentified (Kingston et al., Neuropharmacology 37(1), 1-12, 1998;Johnson et al., Neuropharmacology 38(10), 1519-29, 1999). No appreciablespecific binding of the radio-ligand [3H]-LY341495 (formula given in D.A. Barda et al. 2004) was found in membranes of cells expressing humanmGlu1a, mGlu5a, mGlu4a, mGlu6, or mGlu7a receptors. Many effects inducedby group II receptor agonists could be reversed by this compound. ThusLY341495 also represents a highly selective tool compound.

Positive modulators activate the mGlu2 receptor dependent on thepresence of glutamate (potentiators). Thus, the compound “sensitizes”the receptor to react already at lower concentrations of the ligand.Positive modulators can also activate the mGlu2 receptor directly. ThemGlu receptors consist of a large extracellular N-terminal domain, whichbinds the natural ligand, glutamate, which is homologous to theperiplasmatic amino acid binding proteins from bacteria. This domain islinked to a 7-transmembrane domain. This canonical domain, common to allG-protein coupled receptors, contains the canonical ligand binding sitefor GPCRs (compare rhodopsin in retinal). In the mGluRs this site isfree and may play a role as modulatory site for positive and negativeallosteric compounds.

A hint for the exact amino acid sites responsible for ligand binding ofa model potentiator (LY487379, see Johnson et al., J. Med. Chem. 46(15),3189-92, 2003) come from the amino acid comparison between mGlu2receptor and mGluR3 in this region. As the potentiator is specific formGlu2 receptor, the binding should not take place at mGluR3 and theresponsible amino acids should be exactly the ones which differ betweenthe two receptors. Recently the binding site of a model potentiator(LY487379) has been mapped by site directed mutagenesis. The bindingsite seems to be within the transmembrane domain of mGlu2 receptor(Schaffhauser et al., Mol. Pharmacol. 64(4), 798-810, 2003). Inparticular the amino acids 688, 689 and 735 are indicated for binding.

MGlu2 receptor is expressed in both separate and overlapping circuits ofrelevance for neuropsychiatric and neurological disorders. This includesexpression in neocortex, thalamus, striatum, amygdala and hippocampus.Within these circuits mGlu2 receptor is mainly expressedpresynaptically. As a consequence of this expression pattern it has beenshown that excitatory transmitter release is regulated by group IIagonists in diverse brain regions. For, it has been demonstrated thatgroup II agonists normalize PCP-induced increase of glutamate in theprefrontal cortex (PFC) and that dopamine is regulated by group IIagonists in a region-specific manner. As one function group II agonistsincrease dopamine and metabolites in the PFC. Also serotonin andmetabolites are regulated in the PFC. This has further been demonstratedby a functional antagonism of 5-HT2A receptors in this brain region.

These data indicate that the mGlu2 receptor approach may normalize anumber of de-regulated transmitters in schizophrenia. The mGlu2 receptoragonist/potentiator concept will likely give rise to the opportunity tonormalize

positive symptoms, due to regulation of glutamate,

negative symptoms, due to regulation of dopamine and serotonin, and

cognitive symptoms, due to regulation of acetylcholine in the PFC.

Besides schizophrenia, drug abuse may be an interesting diseaseindication, as group II agonists block of expression of locomotorsensitization by amphetamine, among a multitude of other describedeffects. The usefulness of such compounds is not limited to the diseasestates described above.

The potentiator concept for mGlu2 receptor is relatively new (Barda etal., 2004), but necessary to evaluate the relevance of mGlu2 receptorversus mGluR3. This is of note, as the group II agonists described abovedo cross react with both receptor types. Within the recent years,reports directly demonstrate the relevance of mGlu2 receptor inpsychosis models in rodents by describing function of mGlu2 receptorpotentiators in models of PCP-induced hyperlocomotion,amphetamine-induced hyperlocomotion, and reversal of amphetamine-induceddisruption of PPI in mice (Galici et al., JPET 315(3), 1181-1187, 2005).

Beyond these data, indicating a relevance of mGlu2 receptor potentiatorsin schizophrenia, new reports furthermore demonstrate efficacy of mGlu2receptor potentiators in anxiety, as potentiators have been shown to beefficacious in rat fear-potentiated startle and stress-inducedhyperthermia in mice (Johnson et al. Psychopharmacol, 179(1), 271-83,2005).

A pure NMDA activation approach (the “glutamatergic hypothesis ofschizophrenia”) may result in side effect liabilities. In particularexcitotoxicity is a relevant side effect which needs to be consideredearly within a potential screening cascade of such projects. This sideeffect liability may limit the usefulness of such approaches.

As described above, the mGlu2 receptor positive modulator approach doesnot purely rely on the glutamatergic hypothesis, but likely is involvedin the normalization of release of a number of excitatoryneurotransmitters. Consequently, to date there is no evidence forexcitotoxic liability of group II agonists or mGlu2 receptor positivemodulators. Group II agonists even show the opposite effects. They areneuroprotective in the MPTP model of Parkinson's disease, they reducelow Mg²⁺-induced epileptiform discharges in slice preparations and theyhave anticonvulsant action in acute seizure models.

As a relevant side effect, a negative influence on cognition wasdescribed for group II agonists (Higgins et al., Neuropharmacol 46,907-917, 2004). However, to date this finding is controversial in theliterature. While one group finds a reversal of cognitive deficitsinduced by PCP (Moghaddam and Adams, Science 281(5381), 1349-52, 1998),a second group finds a reduction of DNMTP performance with the mGlu2receptor agonist LY354740, which is not present in mGlu2 receptorknockout mice (Higgins et al., Neuropharmacol. 46, 907-917, 2004). Thisfinding contrasts to the data from Moghaddam and Adams and would alsocontradict the normalization of ACh release in the PFC by this compound(see above).

WO 2006/015158 and WO 2006/047237 describe heterocyclic compoundscarrying an indanone moiety, the compounds being potentiators ofmetabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/030032 describes pyridinone compounds which are potentiators ofmetabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/049969 describes N-(phenyl)aminoalkyl substituted pyrimidinecompounds, which are potentiators of metabotropic glutamate receptors,including the mGlu2 receptor.

WO 2006/057860, WO 2006/057869 and WO 2006/057870 describe compoundscarrying a 4-acyl-3-hydroxy-phenyl moiety. The compounds are suggestedto be potentiators of metabotropic glutamate receptors, including themGlu2 receptor.

WO 2006/091496 describes compounds carrying a benzazole moiety, thecompounds being suggested as potentiators of metabotropic glutamatereceptors, including the mGlu2 receptor.

WO 2006/020879, WO2007/021308 and WO 2007/021309 disclose isoindolonecompounds, which are suggested as potentiators of metabotropic glutamatereceptors, including the mGlu2 receptor.

WO 2008/145616 discloses heterocyclic compounds which are positivemodulators of metabotropic receptors, including the mGlu2 receptor.

WO 2008/130853 discloses heterocyclic hydrazides and their use asmetabotropic glutamate receptor potentiators.

Although the compounds of prior art have a high affinity with regard tothe mGlu2 receptor, their receptor binding profile and/or theirpharmacological profile is not always satisfactory. In particular, thecompounds often have poor selectivity with regard to mGlu2 receptor incomparison with mGlu3 or group III mGlu receptors or are glutamateagonists. Moreover, the potentiators are in terms of (i) bindingaffinity, (ii) receptor potentiation and/or stimulation profile, (iii)selectivity versus other receptors, (iv) physicochemical properties, (v)in vitro microsomal stability and (vi) pharmacokinetic parameterssuboptimal.

It is an object of the present invention to provide further compoundswhich are potentiators of metabotropic glutamate receptors, inparticular of the mGlu2 receptor, and which thus are useful in thetreatment or prevention of neurological and psychiatric disordersassociated with glutamate dysfunction and diseases in which metabotropicglutamate receptors are involved. In particular, such diseases arecentral nervous system disorders selected from the group ofschizophrenia, drug abuse, anxiety, migraine, depression and epilepsyand the like.

These and further objects are solved by the compounds of the generalformula I, as described herein, as well as by the N-oxides thereof, andby their pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION

The present invention thus provides compounds of formula I

wherein

-   -   X² is N or C—R²    -   X³ is N or C—R³    -   X⁴ is N or C—R⁴    -   provided that none or one of X², X³ or X⁴ is N;    -   Y¹ is N, C or C—R⁵    -   Y² is N, C or C—R⁶    -   Y³ is N, C or C—R⁷    -   Y⁴ is N, C or C—R⁸    -   provided that only the moiety Y¹, Y², Y³ or Y⁴ to which Z is        bound is C and Y²,    -   further provided at most one of Y¹, Y², Y³ or Y⁴ is N;    -   Z is O, S, S(O), S(O)₂ or NR^(Z);        -   R^(Z) is hydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,            C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, which is unsubstituted            or carries one radical selected from C₁-C₄-alkoxy and            NR^(Z1)R^(Z2);            -   where R^(Z1) and R^(Z2) are independently of each other                selected from hydrogen, C₃-C₆-cycloalkyl,                C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl and                C₁-C₄-alkoxy-C₁-C₄-alkyl, or            -   R^(Z1) and R^(Z2) together with the nitrogen to which                they are attached form a 5- or 6-membered N-bound                saturated heterocycle, which, in addition to the                nitrogen atom may comprise a further heteroatom,                selected from O, S and N as ring member and which is                unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl                radicals;        -   or R^(Z) is a radical SO₂R^(Z3) or a radical            S(O)₂NR^(Z4)R^(Z5);            -   where R^(Z3) is C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,                C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,                C₃-C₆-cycloalkylmethyl, phenyl or benzyl, wherein the                phenyl ring in the last two mentioned radicals itself is                unsubstituted or carries 1, 2, 3, 4 or 5 identical or                different radicals selected from halogen, C₁-C₄-alkyl,                C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,            -   R^(Z4) and R^(Z5) have one of the meanings given for                R^(Z1) and R^(Z2);    -   Q is CH₂ or CH₂CH₂, where one or two of the hydrogen atoms in        CH₂ or CH₂CH₂ may be replaced by halogen, C₁-C₄-alkyl or        C₁-C₄-haloalkyl;    -   R¹ is hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,        C₁-C₆-alkoxy, C₁-C₄-haloalkoxy, C₃-C₈-cycloalkyl, a radical        NR^(1a)R^(1b), C-bound 3- to 7-membered, saturated heterocyclyl        having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected        from O and S, as ring members, aryl, aryl-CH₂, aryloxy, hetaryl,        hetaryloxy or hetaryl-CH₂, wherein the heterocyclyl, aryl and        hetaryl rings ring in the last seven radicals themselves are        unsubstituted or carry 1, 2, 3, 4 or 5 identical or different        radicals R^(1c);        -   R^(1a) is hydrogen, C₁-C₈-alkyl, C₁-C₈-haloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl,            C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, benzyl, phenyl or            5- or 6-membered hetaryl, wherein the phenyl and hetaryl            rings in the last three radicals itself are unsubstituted or            carry 1, 2, 3, 4 or 5 identical or different radicals            R^(1c);        -   R^(1b) is hydrogen or C₁-C₄-alkyl; or        -   NR^(1a)R^(1b) is a 3- to 10-membered, in particular 5- to            10-membered, mono- or bicyclic N-bound saturated            heterocycle, which, in addition to the nitrogen atom may            comprise a further heteroatom, selected from O, S and N as            ring member and which is unsubstituted or carries 1, 2, 3 or            4 radicals R^(1c);        -   R^(1c) is selected from the group consisting of halogen, CN,            OH, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular            C₁-C₄-alkyl;    -   R², R³ and R⁴ are, independently of each other, selected from        hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,        phenyl, C₁-C₄-haloalkoxy, a radical (CH₂)_(n)NR′R″, where R′ and        R″ have one of the meanings given for R^(Z1) and R^(Z2) and        wherein n is 0, 1, 2, 3 or 4,        -   or C-bound 3- to 10-membered, in particular 3- to 7-membered            saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or            1 heteroatoms, selected from O and S, as ring members, where            the heterocyclyl itself is unsubstituted or carries 1, 2, 3,            4 or 5 identical or different radicals R^(6c), where R^(6c)            has one of the meanings given for R^(1c);    -   R⁵ is hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkoxy,        (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given        for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, in        particular 1,        -   or C-bound 3- to 10-membered, in particular 3- to 7-membered            saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or            1 heteroatoms, selected from O and S, as ring members, where            the heterocyclyl itself is unsubstituted or carries 1, 2, 3,            4 or 5 identical or different radicals R^(6c), where R^(6c)            has one of the meanings given for R^(1c);    -   R⁶, R⁷, R⁸ are, independently of each other, selected from        hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,        (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given        for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, or        C-bound 3- to 10-membered, in particular 3- to 7-membered        saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1        heteroatoms, selected from O and S, as ring members, where the        heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5        identical or different radicals R^(6c) where R^(6c) has one of        the meanings given for R^(1c);    -   R^(a) is C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkyl, which        is unsubstituted or carries one radical selected from        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and a radical NR^(a1)R^(a2),        -   where R^(a1) and R^(a2) are independently of each other            selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,            C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   a radical NR^(a3)R^(a4) or a radical N═C(R^(a5))R^(a6),            where        -   R^(a3) and R^(a5) are independently of each other selected            from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and            C₁-C₄-alkoxy-C₁-C₄-alkyl;        -   R^(a4) and R^(a6) are independently of each other selected            from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 10-membered, in            particular 3- to 7-membered saturated heterocyclyl, 3- to            10-membered, in particular 3- to 7-membered saturated            heterocyclylmethyl, where heterocyclyl in the last two            mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1            heteroatoms, selected from O and S, as ring members,            -   aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the                heterocyclyl, aryl and hetaryl rings ring in the last                six radicals themselves are unsubstituted or carry 1, 2,                3, 4 or 5 identical or different radicals R^(ac) where                R^(ac) has one of the meanings given for R^(1c);    -   R^(b) is hydrogen, halogen or C₁-C₄-alkyl;    -   and the N-oxides and the pharmaceutically acceptable salts        thereof.

The compounds of the present invention are potentiators of metabotropicglutamate (mGlu) receptor function, in particular they are potentiatorsof mGlu2 receptors. That is, the compounds of the present invention donot appear to bind at the glutamate recognition site on the mGlureceptor, but in the presence of glutamate or a glutamate agonist, thecompounds of the present invention increase mGlu receptor response. Thepresent potentiators are expected to have their effect at mGlu receptorsby virtue of their ability to increase the response of such receptors toglutamate or glutamate agonists, enhancing the function of thereceptors. It is recognized that the compounds of the present inventionwould be expected to increase the effectiveness of glutamate andglutamate agonists of the mGlu2 receptor. Thus, the compounds of thepresent invention are expected to be useful in the treatment of variousneurological and psychiatric disorders associated with glutamatedysfunction described to be treated herein and others that can betreated by such positive modulators as are appreciated by those skilledin the art.

The present invention also relates to pharmaceutical compositionscomprising at least one compound of the formula I, an N-oxide thereofand/or a pharmaceutically acceptable salt thereof, optionally togetherwith at least one physiologically acceptable carrier or auxiliarysubstance.

The present invention also relates to a method for treating a medicaldisorder, selected from neurological and psychiatric disordersassociated with glutamate dysfunction, said method comprisingadministering an effective amount of at least one compound of theformula I, an N-oxide thereof and/or a pharmaceutically acceptable saltthereof to a subject in need thereof.

The present invention also relates to a method for potentiation ofmetabotropic glutamate receptor activity in a mammal which comprisesadministering an effective amount of at least one compound of theformula I, an N-oxide thereof and/or a pharmaceutically acceptable saltthereof.

The present invention also relates to the use of the compounds offormula I, an N-oxide thereof and/or a pharmaceutically acceptable saltthereof, in therapy of a disease mentioned herein.

The compounds of the formula I, their N-oxides and theirpharmaceutically acceptable salts are particularly useful for preparing

-   -   a medicament for treating, controlling, ameliorating or reducing        the risk of anxiety in a mammalian;    -   a medicament for preparing a medicament for treating,        controlling, ameliorating or reducing the risk of depression in        a mammalian; a medicament for treating, controlling,        ameliorating or reducing the risk of migraine in a mammalian;    -   a medicament for treating, controlling, ameliorating or reducing        the risk of schizophrenia in a mammalian;    -   a medicament for treating, controlling, ameliorating or reducing        the risk of epilepsy in a mammalian;    -   a medicament for treating or ameliorating the symptoms        associated with substance-related disorders in a mammalian.

The present invention also relates to

-   -   a method for treating, controlling, ameliorating or reducing the        risk of anxiety in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of depression in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of schizophrenia in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of epilepsy in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of migraine in a mammalian;    -   a method for treating or ameliorating the symptoms associated        with substance-related disorders in a mammalian;

which methods comprising administering an effective amount of at leastone compound of the formula I, an N-oxide thereof and/or apharmaceutically acceptable salt thereof to a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. The independentsyntheses of these diastereomers or their chromatographic separationsmay be achieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated, so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the conversion of theenantiomeric mixture of compounds I into a diastereomeric mixture, e.g.by reaction with a chiral auxiliary, such as a chiral acid or base,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Theenantiomeric mixture of the compounds can also be separated directly bychromatographic methods utilizing chiral stationary phases, whichmethods are well known in the art. Alternatively, any enantiomer of acompound may be obtained by stereoselective synthesis using opticallypure starting materials or reagents of known configuration by methodswell known in the art.

The term “pharmaceutically acceptable salts” refers to cationic oranionic salts compounds, wherein the counter ion is derived frompharmaceutically acceptable non-toxic bases or acids including inorganicor organic bases and inorganic or organic acids.

When the compound of formula I is acidic, salts may be prepared frompharmaceutically acceptable non-toxic bases, including inorganic andorganic bases. Salts derived from inorganic bases include salts, whereinthe counter ion is aluminium, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic, manganous, potassium, sodium,zinc ion and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium ions. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, trifluoroaceticacid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicacid, and the like. Particularly preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof formula I are meant to also include the pharmaceutically acceptablesalts.

The present invention moreover relates to compounds of formula I asdefined above, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Of course, the compounds according to the invention contain more of therespective isotope than this naturally occurs and thus is anyway presentin the compounds I.

The compounds of the formula I and their salts in the solid form mayexist in more than one crystal structure (polymorphism), and may also bein the form of hydrates or other solvates. The present inventionincludes any polymorph of the compound I or its salt as well as anyhydrate or other solvate.

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine, in particular fluorine, chlorine or bromine.

The term “alkyl” as used herein and in the alkyl moieties ofalkoxyalkyl, alkylamino, dialkylamino and alkylsulfonyl denotes in eachcase a straight-chain or branched alkyl group having usually from 1 to 8carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4carbon atoms, in particular 1 to 2 carbon atoms. Examples of an alkylgroup are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl,iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl,1-propylpentyl, n-octyl, 1-methyloctyl, 2-methylheptyl, 1-ethylhexyl,2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl and 2-propylpentyl.

The term “haloalkyl” as used herein and in the haloalkyl moieties ofhaloalkylsulfonyl, denotes in each case a straight-chain or branchedalkyl group having usually from 1 to 8 carbon atoms, frequently from 1to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 2carbon atoms, wherein the hydrogen atoms of this group are partially ortotally replaced with halogen atoms. Preferred haloalkyl moieties areselected from C₁-C₄-haloalkyl, more preferably from C₁-C₂-haloalkyl, inparticular from C₁-C₂-fluoroalkyl such as fluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, pentafluoroethyl or C₁-C₄-fluoroalkyl such asfluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl,2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoro-1-trifluormethylethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and the like.

The term “alkoxy” as used herein denotes in each case a straight-chainor branched alkyl group which is bound via an oxygen atom and hasusually from 1 to 8 carbon atoms, frequently from 1 to 6 carbon atoms,preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy,ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy,tert-butyloxy, pentyloxy, 1-methylbutyloxy, 2-methylbutyloxy,3-methylbutyloxy, 2,2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy,1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, 1-methylpentyloxy,2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy,1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy,2,2-dimethylbutyloxy, 2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy,1-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropyloxy,1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy,1-ethyl-2-methylpropyloxy n-heptyloxy, 1-methylhexyloxy,2-methylhexyloxy, 3-methylhexyloxy, 4-methylhexyloxy, 5-methylhexyloxy,1-ethylpentyloxy, 2-ethylpentyloxy, 3-ethylpentyloxy, 1-propylpentyloxy,n-octyloxy, 1-methyloctyloxy, 2-methylheptyloxy, 1-ethylhexyloxy,2-ethylhexyloxy, 1,2-dimethylhexyloxy, 1-propylpentoxy and2-propylpentyloxy.

The term “haloalkoxy” as used herein denotes in each case astraight-chain or branched alkoxy group having from 1 to 8 carbon atoms,frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, inparticular 1 or 2 carbon atoms, wherein the hydrogen atoms of this groupare partially or totally replaced with halogen atoms, in particularfluorine atoms. Preferred haloalkoxy moieties include C₁-C₄-haloalkoxy,in particular C₁-C₂-fluoroalkoxy, such as fluoromethoxy,difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluorethoxy,2,2,2-trichloroethoxy, pentafluoroethoxy and the like.

The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein denotes in each casea straight-chain or branched alkyl group which is bound via an oxygenatom to another alkyl group. Both alkyl groups have usually from 1 to 4carbon atoms, frequently from 1 to 3 carbon atoms, preferably 1 to2-carbon atoms. Examples are methoxymethyl, methoxyethyl,methoxy-n-propyl, methoxy-n-butyl, ethoxymethyl, ethoxyethyl,ethoxy-n-propyl, ethoxy-n-butyl, n-propoxymethyl, n-propoxyethyl,n-propoxy-n-propyl, n-propoxy-n-butyl, n-butoxymethyl, n-butoxyethyl,n-butoxy-n-propyl, n-butoxy-n-butyl.

The term “cycloalkyl” as used herein denotes in each case a mono- orbicyclic cycloaliphatic radical having usually from 3 to 8 C atoms or 3to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl,bicyclo[2.2.1]heptyl, and bicycle[2.2.2]octyl.

The term “cycloalkylmethyl” as used herein denotes in each case a methylradical which is bound to a cycloalkyl group as defined above. Examplesare cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, especiallycyclopropylmethyl.

The term “aryl” as used herein denotes in each case a cyclic radicalselected from the group consisting of mono-, bi- or tricyclic aromaticradicals. Examples are phenyl, naphthyl and anthracyl, especiallyphenyl.

The term “aryl-CH₂” as used herein denotes in each case a methylradical, which is bound to an aryl group as described above. Examplesare benzyl, naphthylmethyl and anthracylmethyl, especially benzyl.

The term “aryloxy” as used herein denotes in each case an aryl groupwhich is bound via an oxygen atom. Examples are phenoxy, naphthoxy andanthracyloxy, especially phenoxy.

The term “hetaryl” as used herein denotes in each case a heterocyclicradical selected from the group consisting of monocyclic 5- or6-membered heteroaromatic radicals comprising as ring members 1, 2 or 3heteroatoms selected from N, O and S. Examples of 5- or 6-memberedheteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl,pyrimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2- or3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2-,3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl,pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1,3,4]oxadiazolyl, 4- or5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or5-(1,3,4-oxadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1,3,4-thiadiazol)yl,4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl,e.g. 1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or4H-1,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl.

The term “hetaryl-CH₂” as used herein denotes in each case a methylradical, which is bound to a hetaryl group as described above. Examplesare methylpyridyl, i.e. 2-, 3-, or 4-methylpyridyl, methylpyrimidinyl,i.e. 2-, 4- or 5-methylpyrimidinyl, methylpyrazinyl, methylpyridazinyl,i.e. 3- or 4-methylpyridazinyl, methylthienyl, i.e. 2- or3-methylthienyl, methylfuryl, i.e. 2- or 3-methylfuryl, methylpyrrolyl,i.e. 2- or 3-methylpyrrolyl, methyloxazolyl, i.e. 2-, 3- or5-methyloxazolyl, methylisoxazolyl, i.e. 3-, 4- or 5-methylisoxazolyl,methylthiazolyl, i.e. 2-, 3- or 5-methylthiazolyl, methylisothiazolyl,i.e. 3-, 4- or 5-methylisothiazolyl, methylpyrazolyl, i.e. 1-, 3-, 4- or5-methylpyrazolyl, i.e. 1-, 2-, 4- or 5-methylimidazolyl,methyloxadiazolyl, methylthiadiazolyl, methyltriazolyl andmethyltetrazolyl, i.e. 1H- or 2H-tetrazolyl.

N-bound heterocycles comprise saturated, non-aromatic heterocyclicrings, which are bound via the nitrogen-ring atom. It is 3- to10-membered and mono- or bicyclic, especially it is a 3- to 7-memberedmonocyclic ring. Examples therefore include aziridinyl, azetidinyl,azepanyl, azocanyl, azonanyl, azecanyl, pyrrolidinyl, piperidinyl,imidazolidinyl, pyrazolidinyl, piperazinyl, diazepanyl, diazocanyl,diazonanyl, diazecanyl, oxazolidinyl, isoxazolidinyl, morpholinyl,oxazinanyl, oxazepanyl, oxazocanyl, oxazonanyl, oxazecanyl,thiazolidinyl, isothiazolidinyl, thiazinanyl, thiomorpholinyl,thiazepanyl, thiazocanyl, thiazonanyl, thiazecanyl, oxadiazinanyl,oxadiazepanyl, oxadiazocanyl, oxadiazonanyl, oxadiazecanyl,thiodiazinanyl, thiadiazepanyl, thiadiazocanyl, thiadiazonanyl,thiadiazecanyl, decahydroquinolinyl, decahydroquinazolinyl,deachydronathyridinyl and the like.

The term “C-bound saturated heterocyclyl” as used herein denotes in eachcase a C-bound heterocyclic radical which is 3- to 10-membered,saturated and having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms,selected from O and S, as ring members. Especially it is 3- to7-membered, monocyclic radical having 1 or 2 nitrogen atoms and 0 or 1heteroatoms, selected from O and S, as ring members. The heterocyclylitself can be unsubstituted or substituted. Examples therefore includeaziridinyl, azetidinyl, azepanyl, azocanyl, azonanyl, azecanyl,pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl,diazepanyl, diazocanyl, diazonanyl, diazecanyl, oxazolidinyl,isoxazolidinyl, morpholinyl, oxazinanyl, oxazepanyl, oxazocanyl,oxazonanyl, oxazecanyl, thiazolidinyl, isothiazolidinyl, thiazinanyl,thiomorpholinyl, thiazepanyl, thiazocanyl, thiazonanyl, thiazecanyl,oxadiazinanyl, oxadiazepanyl, oxadiazocanyl, oxadiazonanyl,oxadiazecanyl, thiodiazinanyl, thiadiazepanyl, thiadiazocanyl,thiadiazonanyl, thiadiazecanyl, decahydroquinolinyl,decahydroquinazolinyl, deachydronathyridinyl and the like.

Preferred compounds of the invention are those, wherein the variablesR¹, R^(a), R^(b), Q, Z, X², X³ and X⁴ in formula I independently of eachother preferably in any combination have one of the following meanings:

The radical R¹ is selected from the group consisting of hydrogen,halogen, in particular chlorine or bromine, C₁-C₆-alkyl, in particularbranched C₃-C₆-alkyl such as isopropyl, isobutyl or tert.-butyl,C₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂,CH₂CF₃ or CF₂CF₃, C₁-C₆-alkoxy, in particular C₁-C₃-alkoxy, such asmethoxy, ethoxy, n-propoxy, isopropoxy, C₁-C₄-haloalkoxy, in particularC₁-C₂-fluoroalkoxy, such as OCF₃ or OCHF₂, C₃-C₈-cycloalkyl, inparticular C₃-C₆-cycloalkyl, such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, a radical NR^(1a)R^(1b), wherein R^(1a) andR^(1b) are as defined above and wherein at least one of R^(1a) andR^(1b), in particular both R^(1a) and R^(1b), are different fromhydrogen, aryl, in particular phenyl, aryl-CH₂, in particular benzyl,aryloxy, in particular phenoxy, and hetaryl, in particular pyridinyl,pyrimidinyl, thienyl or furyl, wherein the aryl, in particular phenylring, and hetaryl rings in the aforementioned four radicals itself isunsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicalsR^(1c).

In a particular embodiment of the invention, R¹ is selected from thegroup consisting of phenyl and phenoxy, wherein the phenyl ring in thelast two radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(1c).

In another particular embodiment of the invention, R¹ is selected fromthe group consisting of branched C₃-C₆-alkyl, such as tert.-butyl,C₁-C₆-alkoxy, C₁-C₄-haloalkoxy, C₃-C₆-cycloalkyl and C₁-C₆-haloalkyl, inparticular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂, CH₂CF₃ or CF₂CF₃.

In another particular embodiment of the invention, R¹ is linearC₁-C₆-alkyl such as methyl, ethyl, n-propyl or n-butyl.

In another particular embodiment of the invention, R¹ is halogen such asiodine, or chlorine.

In a further particular embodiment of the invention, R¹ is a radicalNR^(1a)R^(1b) or C-bound 3- to 7-membered, saturated heterocyclyl having1 or 2 nitrogen atoms and 0 or 1 heteroatom, selected from O and S, asring members, where the heterocyclyl itself is unsubstituted or carries1, 2, 3, 4 or 5 identical or different radicals R^(1c). In this furtherparticular embodiment, R¹ is especially a radical NR^(1a)R^(1b), whereR^(1a) is selected from 2-methoxyethyl, 3-methoxy-n-propyl or2-ethoxyethyl while R^(1b) is methyl or ethyl or the radicalNR^(1a)R^(1b) is morpholinyl, 1,4-oxazepan-4-yl, 4-methylpiperazinyl,1-pyrrolidinyl or 1-piperidinyl or R¹ is 4-methylpiperidin-1-yl or3-methylpyrrolidin-1-yl.

Particular examples of R¹ include CF₃, chloro, fluoro, iodo, amino,tert.-butyl, benzylamino, phenylamino, phenoxy, phenyl, 4-cyanophenyl,4-trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, methoxy,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholin-4-yl,1,4-oxazepan-4-yl, 4-methylpiperazin-1-yl, 1-pyrrolidinyl,1-piperidinyl, 4-methylpiperidin-1-yl, 3-methylpyrrolidin-1-yl,N-(2-methoxyethyl)-N-methylamino, N-(3-methoxy-n-propyl)-N-methylamino,N-(2-ethoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino,N-(3-methoxy-n-propyl)-N-ethylamino or N-(2-ethoxyethyl)-N-ethylamino.

Where present, R^(1a) is particularly selected from the group consistingof hydrogen, C₃-C₈-cycloalkyl, C₁-C₈-alkylcarbonyl, in particular2,2-dimethylpropionyl, C₁-C₈-alkoxycarbonyl, in particulartert-butoxycarbonyl, benzyl, phenyl or 5- or 6-membered hetaryl, whereinthe phenyl and hetaryl rings in the last three radicals itself areunsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicalsR^(1c).

Where present, R^(1b) is preferably hydrogen or C₁-C₄-alkyl.

Where present, NR^(1a)R^(1b) may also preferably be a 5- to 10-membered,in particular 5- or 6-membered, mono- or bicyclic N-bound saturatedheterocycle, which, in addition to the nitrogen atom may comprise afurther heteroatom selected from O, S and N as ring member and which isunsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals, examplesincluding 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl,1-pyrrolidinyl, N-methylpiperazin-1-yl, 1,4-oxazepan-4-yl,4-methylpiperidin-1-yl or 3-methylpyrrolidin-1-yl.

R^(1a) may also preferably be C₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(1b) isC₁-C₄-alkyl. Examples are N-(2-methoxyethyl)-N-methylamino,N-(3-methoxy-n-propyl)-N-methylamino, N-(2-ethoxyethyl)-N-methylamino,N-(2-methoxyethyl)-N-ethylamino, N-(3-methoxy-n-propyl)-N-ethylamino andN-(2-ethoxyethyl)-N-ethylamino.

Where present, R^(1c) is selected from the group consisting of halogen,CN, OH, C₁-C₄-alkyl, such as methyl, ethyl, n-propyl or isopropyl,C₃-C₆-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, C₁-C₄-haloalkyl, in particular CHF₂, CF₃, CH₂CF₃ or CF₂CF₃,C₁-C₄-alkoxy, in particular methoxy or ethoxy, and C₁-C₄-haloalkoxy.

The radical R^(a) is selected from the group consisting ofC₃-C₆-cycloalkyl, in particular C₃-C₄-cycloalkyl, such as cyclopropyl,C₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl such as CF₃, CHF₂,CH₂CF₃, CF₂CF₃, C₁-C₆-alkyl, in particular C₂-C₆-alkyl, especiallyC₃-C₆-alkyl such as n-propyl, n-butyl, iso-butyl, n-pentyl, theaforementioned alkyl radical can be unsubstituted or carries one radicalselected from the group consisting of C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,in particular methoxy, ethoxy or OCF₃. In particular R^(a) is selectedfrom the group consisting of ethyl, n-propyl, n-butyl, cyclopropyl,2-methoxyethyl, 2-ethoxyethyl, 2,2,2-trifluoroethyl and2-trifluoromethoxyethyl. In a particular embodiment of the inventionR^(a) is C₂-C₆-alkyl, especially C₂-C₄-alkyl which carries one radicalselected from the group consisting of C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,in particular methoxy, ethoxy or OCF₃, such as 2-methoxyethyl,2-ethoxyethyl, 2,2,2-trifluoroethyl and 2-trifluoromethoxyethyl. Inanother particular embodiment R^(a) is a radical NR^(a3)R^(a4), whereR^(a3) has one of the aforementioned meanings and is in particularselected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(a4) hasone of the aforementioned meanings and is in particular selected fromelected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to10-membered, in particular 3- to 7-membered saturated heterocyclyl, 3-to 10-membered, in particular 3- to 7-membered saturatedheterocyclylmethyl, where heterocyclyl in the last two mentionedradicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected fromO and S, as ring members, aryl, aryl-CH₂, hetaryl and hetaryl-CH₂,wherein the heterocyclyl, aryl and hetaryl rings ring in the last sixradicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identicalor different radicals R^(ac), where R^(ac) has one of the meanings givenfor R^(1c).

Where present, R^(a1) and R^(a2) are independently of each other inparticular selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl. Especially, R^(a1)is selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl andC₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(a2) is selected from hydrogen andC₁-C₄-alkyl.

Where present, R^(a3) is selected from hydrogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl andC₁-C₄-alkoxy-C₁-C₄-alkyl.

Where present, R^(a4) is selected from hydrogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 10-membered, in particular 3- to7-membered saturated heterocyclyl, 3- to 10-membered, in particular 3-to 7-membered saturated heterocyclylmethyl, where heterocyclyl in thelast two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1heteroatoms, selected from O and S, as ring members, aryl, aryl-CH₂,hetaryl and hetaryl-CH₂, wherein the heterocyclyl, aryl and hetarylrings ring in the last six radicals themselves are unsubstituted orcarry 1, 2, 3, 4 or 5 identical or different radicals R^(ac) whereR^(ac) has one of the meanings given for R^(1c).

The radical R^(b) is hydrogen, halogen or C₁-C₄-alkyl, in particularhydrogen.

The radical Z is preferably selected from the group consisting of O, Sor NR^(Z), in particular O and NR^(Z), especially O and NH.

If Z is a radical NR^(Z), R^(Z) is in particular selected from the groupconsisting of hydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, which is unsubstituted or carriesone radical selected from C₁-C₄-alkoxy and NR^(Z1)R^(Z2), SO₂R^(Z3) or aradical S(O)₂NR^(Z4)R^(Z5).

Where present, R^(Z1) and R^(Z2) are independently of each other inparticular selected from the group consisting of hydrogen,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl andC₁-C₄-alkoxy-C₁-C₄-alkyl. In particular, R^(Z1) and R^(Z2) may also formtogether with the nitrogen to which they are attached a 5- or 6-memberedN-bound saturated heterocycle, which, in addition to the nitrogen atom,may comprise a further heteroatom, selected from O, S and N as ringmember and which is unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkylradicals, examples including 4-morpholinyl, 4-thiomorpholinyl,1-piperidinyl, 1-pyrrolidinyl or N-methylpiperazin-1-yl.

Where present, R^(Z3) is in particular selected from C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, phenyl or benzyl, wherein thephenyl ring in the last two mentioned itself is unsubstituted or carries1, 2, 3, 4 or 5 identical or different radicals selected from halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.Especially, R^(Z3), where present is C₁-C₄-alkyl such as methyl.

Where present, R^(Z4) and R^(Z5) have in particular one of theparticular meanings given for R^(Z1) and R^(Z2).

Q is CH₂ or CH₂CH₂, in particular CH₂.

In a particular embodiment of the invention, X² is C—R², where R² is asdefined above and R² is in particular selected from the group consistingof hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy or a radical (CH₂)_(n)NR′R″,wherein n is 0 or 1. R′ and R″ have one of the meanings given for R^(Z1)and R^(Z2). Especially R² is hydrogen, i.e. X² is C—H. In thisparticular embodiment, X³ is C—R³ and X⁴ is C—R⁴ or one of X³ and X⁴ mayalso be N. In this embodiment, particular preference is given tocompounds, wherein X³ is C—R³ and X⁴ is C—R⁴. Where occurring, R³ and R⁴are as defined above, and in particular selected, independently of eachother, from the group consisting of hydrogen, halogen, C₁-C₄-alkyl andC₁-C₄-alkoxy, especially from the group consisting of hydrogen,chlorine, methyl and methoxy.

In a particular embodiment of the invention X² is N. If X² is N then X³is C—R³ and X⁴ is C—R⁴, where R³ and R⁴ are as defined above and inparticular selected, independently of each other, from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy,especially from the group consisting of hydrogen, chlorine, methyl andmethoxy.

X³ is in particular C—R³, where R³ is as defined above and wherein R³ isin particular selected from the group consisting of hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting ofhydrogen, chlorine, bromine, methyl and methoxy.

X⁴ is in particular C—R⁴, where R⁴ is as defined above and wherein R⁴ isin particular selected from the group consisting of hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting ofhydrogen, chlorine, methyl and methoxy.

A first particular embodiment of the invention relates to compoundsaccording to formula I, their salts and N-oxides, where X², X³ and X⁴are CR², CR³ and CR⁴, respectively, wherein R², R³ and R⁴ are as definedabove. In this particular embodiment, R² is in particular hydrogen. Inthis particular embodiment, R³ is in particular selected from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy,especially from the group consisting of hydrogen, chlorine, bromine,methyl and methoxy. In this particular embodiment, R⁴ is in particularselected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl andC₁-C₄-alkoxy, especially from the group consisting of hydrogen,chlorine, methyl and methoxy. Especially one or both of the radicals R³and R⁴ are different from hydrogen while R² is hydrogen, with aparticular preference given to compounds, wherein R³ is hydrogen and R⁴is halogen such as chlorine.

In a second particular embodiment according to compounds of formula I,their salts and N-oxides X² is N while X³ and X⁴ are CR³ and CR⁴,respectively, wherein R³ and R⁴ are as defined above. In this particularembodiment, R³ is in particular selected from the group consisting ofhydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from thegroup consisting of hydrogen, chlorine, methyl and methoxy. In thisparticular embodiment, R⁴ is in particular selected from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy,especially from the group consisting of hydrogen, chlorine, methyl andmethoxy. Especially one or both of the radicals R³ and R⁴ are differentfrom hydrogen, with a particular preference given to compounds, whereinR³ is hydrogen and R⁴ is halogen such as chlorine.

In a third embodiment according to compounds of formula I, their saltsand N-oxides X³ is N and X² and X⁴ are CR² and CR⁴, respectively,wherein R² and R⁴ are as defined above. In this particular embodiment,R² is in particular hydrogen. In this particular embodiment, R⁴ is inparticular selected from the group consisting of hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the group consisting ofhydrogen, chlorine, methyl and methoxy.

A further embodiment of the invention relates to compounds of formula I,their salts and N-oxides, wherein X⁴ is N and X² and X³ are CR² and CR³,respectively, wherein R² and R³ are as defined above. In this particularembodiment, R² is in particular hydrogen. In this particular embodiment,R³ is in particular selected from the group consisting of hydrogen,halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the groupconsisting of hydrogen, chlorine, bromine, methyl and methoxy.

Furthermore, one embodiment of the invention relates to compounds offormula I, their salts and N-oxides, wherein Z is bound to Y¹, i.e. Y¹is C, Y² is C—R⁶, Y³ is C—R⁷ and Y⁴ is C—R⁸ or one of Y², Y³ or Y⁴ mayalso be N. Where occurring, R⁶, R⁷ and R⁸ are independently of eachother selected from hydrogen, halogen, C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y² is C—R⁶, Y³ is C—R⁷ and Y⁴ isC—R⁸. In this particular embodiment, R⁶, R⁷ and R⁸ are especiallyhydrogen.

Another embodiment of the invention relates to compounds of formula I,their salts and N-oxides, wherein Z is bound to Y², i.e. Y² is C, Y¹ isC—R⁵, Y³ is C—R⁷ and Y⁴ is C—R⁸ or one of Y¹, Y³ or Y⁴ may also be N.Where occurring, R⁵, R⁷ and R⁸ are independently of each otherpreferably selected from hydrogen, halogen, C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y¹ is C—R⁵, Y³ is C—R⁷ and Y⁴ isC—R⁸. In this particular embodiment R⁵ is in particular hydrogen,chlorine, methyl, or methoxy, especially hydrogen. In this particularembodiment R⁷ and R⁸ are especially hydrogen.

Another embodiment of the invention relates to compounds of formula I,their salts and N-oxides, wherein Z is bound to Y³, i.e. Y³ is C, Y¹ isC—R⁵, Y² is C—R⁶ and Y⁴ is C—R⁸ or one of Y¹, Y³ or Y⁴ may also be N.Where occurring, R⁵, R⁶ and R⁸ are independently of each otherpreferably selected from hydrogen, halogen, C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y¹ is C—R⁵, Y² is C—R⁶ and Y⁴ isC—R⁸. In this particular embodiment, R⁵ is in particular hydrogen,chlorine, methyl, or methoxy, especially hydrogen. In this particularembodiment, R⁷ and R⁸ are especially hydrogen.

Another embodiment of the invention relates to compounds of formula I,their salts and N-oxides, wherein Z is bound to Y⁴, i.e. Y⁴ is C, Y¹ isC—R⁵, Y² is C—R⁶ and Y³ is C—R⁷ or one of Y¹, Y² or Y³ may also be N.Where occurring, R⁵, R⁶ and R⁷ are independently of each otherpreferably selected from hydrogen, halogen, C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y¹ is CR⁵, Y² is CR⁶ and Y³ isC—R⁷. In this particular embodiment, R⁵ is in particular hydrogen,chlorine, methyl, or methoxy, especially hydrogen. In this particularembodiment, R⁶ and R⁷ are especially hydrogen.

An especially preferred embodiment of the present invention relates tocompounds of the formula I, to their salts and to the N-oxides, whereinX² is CH, X³ is C—R³ and X⁴ is C—R⁴, where the radicals R³ and R⁴ are asdefined above and in particular selected from hydrogen, chlorine, methylor methoxy. Especially one or both of the radicals R³ and R⁴ aredifferent from hydrogen, with a particular preference given tocompounds, wherein R³ is hydrogen and R⁴ is halogen, such as chlorine.Amongst these, particular preference is given to compounds, wherein Y¹is C—R⁵, Y² is C, Y³ is C—R⁷ and Y⁴ is N or C—R⁸ or wherein Y¹ is C—R⁵,Y³ is C, Y² is C—R⁶ and Y⁴ is N or C—R⁸. In this especially preferredembodiment, Y⁴ is in particular C—R⁸. In this especially preferredembodiment, R⁵, R⁶, R⁷ and R⁸, where occurring, are as defined above. Inthis especial embodiment, R⁵ is in particular hydrogen, chlorine,methyl, or methoxy, especially hydrogen. In this especial embodiment,R⁶, R⁷ and R⁸ are especially hydrogen. In this especially preferredembodiment, R¹, Q, Z, R^(a) and R^(b) are as defined above and have inparticular one of the preferred, particular or especially givenmeanings.

Another especially preferred embodiment of the present invention relatesto compounds of the formula I, to their salts and to the N-oxides,wherein X² is N, X³ is C—R³ and X⁴ is C—R⁴, where the radicals R³ and R⁴are as defined above and in particular selected from hydrogen, chlorine,methyl or methoxy. Especially one or both of the radicals R³ and R⁴ aredifferent from hydrogen, with a particular preference given tocompounds, wherein R³ is hydrogen and R⁴ is halogen, such as chlorine.Amongst these, particular preference is given to compounds, wherein Y¹is C—R⁵, Y² is C, Y³ is C—R⁷ and Y⁴ is N or C—R⁸ or wherein Y¹ is C—R⁵,Y³ is C, Y² is C—R⁶ and Y⁴ is N or C—R⁸. In this especially preferredembodiment, Y⁴ is in particular C—R⁸. In this especially preferredembodiment, R⁵, R⁶, R⁷ and R⁸, where occurring, are as defined above. Inthis especial embodiment, R⁵ is in particular hydrogen, chlorine,methyl, or methoxy, especially hydrogen. In this especial embodiment,R⁶, R⁷ and R⁸ are especially hydrogen. In this especial embodiment,R^(b) is especially hydrogen. In this especially preferred embodiment,R¹, Q, Z, and R^(a) are as defined above and have in particular one ofthe preferred, particular or especially given meanings.

The compounds of the general formulae Ia and Ib, wherein Z, Q, R¹, R³,R⁴, R⁵ and R^(a) are as defined above and their pharmaceuticallyacceptable salts, represent per se especially preferred embodiments ofthe present invention.

Particular examples of compounds of the general formulae Ia and Ib areindicated in the Table 1-28 below. The meanings for R¹, R³, R⁴ and R⁵indicated in Table A below represent embodiments of the invention whichare likewise preferred independently of one another and especially incombination.

TABLE 1 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 2 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 3 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 4 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 5 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹, R³, R⁴and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 6 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³, R⁴ andR⁵ for a compound in each case corresponds to one line of Table A.

TABLE 7 Compounds of the formulae Ia and Ib in which Z is O, Q is CH₂and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ and R⁵ fora compound in each case corresponds to one line of Table A.

TABLE 8 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 9 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 10 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 11 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 12 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹, R³, R⁴and R⁵ for a compound in each case corresponds to one line of Table A.

TABLE 13 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³, R⁴ andR⁵ for a compound in each case corresponds to one line of Table A.

TABLE 14 Compounds of the formulae Ia and Ib in which Z is NH, Q is CH₂and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ and R⁵ fora compound in each case corresponds to one line of Table A.

TABLE 15 Compounds of the formulae Ia and Ib in which Z is O, Q isCH₂CH₂ and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 16 Compounds of the formulae Ia and Ib in which Z is O, Q isCH₂CH₂ and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ fora compound in each case corresponds to one line of Table A.

TABLE 17 Compounds of the formulae Ia and Ib in which Z is O, Q isCH₂CH₂ and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ fora compound in each case corresponds to one line of Table A.

TABLE 18 Compounds of the formulae Ia and Ib in which Z is O, Q isCH₂CH₂ and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵for a compound in each case corresponds to one line of Table A.

TABLE 19 Compounds of the formulae Ia and Ib in which Z is O, Q isCH₂CH₂ and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹,R³, R⁴ and R⁵ for a compound in each case corresponds to one line ofTable A.

TABLE 20 Compounds of the formulae Ia and Ib in which Z is O, Q isCH₂CH₂ and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³,R⁴ and R⁵ for a compound in each case corresponds to one line of TableA.

TABLE 21 Compounds of the formulae Ia and Ib in which Z is O, Q isCH₂CH₂ and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ andR⁵ for a compound in each case corresponds to one line of Table A.

TABLE 22 Compounds of the formulae Ia and Ib in which Z is NH, Q isCH₂CH₂ and R^(a) is C₂H₅ and the combination of R¹, R³, R⁴ and R⁵ for acompound in each case corresponds to one line of Table A.

TABLE 23 Compounds of the formulae Ia and Ib in which Z is NH, Q isCH₂CH₂ and R^(a) is n-C₃H₇ and the combination of R¹, R³, R⁴ and R⁵ fora compound in each case corresponds to one line of Table A.

TABLE 24 Compounds of the formulae Ia and Ib in which Z is NH, Q isCH₂CH₂ and R^(a) is n-C₄H₉ and the combination of R¹, R³, R⁴ and R⁵ fora compound in each case corresponds to one line of Table A.

TABLE 25 Compounds of the formulae Ia and Ib in which Z is NH, Q isCH₂CH₂ and R^(a) is cyclopropyl and the combination of R¹, R³, R⁴ and R⁵for a compound in each case corresponds to one line of Table A.

TABLE 26 Compounds of the formulae Ia and Ib in which Z is NH, Q isCH₂CH₂ and R^(a) is 2-(trifluoromethoxy)ethyl and the combination of R¹,R³, R⁴ and R⁵ for a compound in each case corresponds to one line ofTable A.

TABLE 27 Compounds of the formulae Ia and Ib in which Z is NH, Q isCH₂CH₂ and R^(a) is 2,2,2-trifluoroethyl and the combination of R¹, R³,R⁴ and R⁵ for a compound in each case corresponds to one line of TableA.

TABLE 28 Compounds of the formulae Ia and Ib in which Z is NH, Q isCH₂CH₂ and R^(a) is 2-methoxyethyl and the combination of R¹, R³, R⁴ andR⁵ for a compound in each case corresponds to one line of Table A.

TABLE A No. R¹ R³ R⁴ R⁵ A1 H H H H A2 CH₃ H H H A3 C₂H₅ H H H A4 n-C₃H₇H H H A5 n-C₄H₉ H H H A6 n-C₅H₁₁ H H H A7 n-C₆H₁₃ H H H A8 CF₃ H H H A9CH₂CF₃ H H H A10 OCH₃ H H H A11 OCH₂—CH₃ H H H A12 OCH₂—CH₂—CH₃ H H HA13 OCH₂—CH₂—CH₂—CH₃ H H H A14 OCF₃ H H H A15 OCHF₂ H H H A16 OCH₂—CF₃ HH H A17 Phenyl H H H A18 Phenoxy H H H A19 Benzyl H H H A20 Cl H H H A21Br H H H A22 I H H H A23 NH₂ H H H A24 NH-Phenyl H H H A25 CN H H H A26NH-Benzyl H H H A27 4-cyanophenyl H H H A28 1,4-oxazepan-4-yl H H H A294-Morpholinyl H H H A30 4-Methylpiperazin-1-yl H H H A31N(2-methoxyethyl)(methyl) H H H A32 N(3-methoxypropyl)(methyl) H H H A33H Cl H H A34 CH₃ Cl H H A35 C₂H₅ Cl H H A36 n-C₃H₇ Cl H H A37 n-C₄H₉ ClH H A38 n-C₅H₁₁ Cl H H A39 n-C₆H₁₃ Cl H H A40 CF₃ Cl H H A41 CH₂CF₃ Cl HH A42 OCH₃ Cl H H A43 OCH₂—CH₃ Cl H H A44 OCH₂—CH₂—CH₃ Cl H H A45OCH₂—CH₂—CH₂—CH₃ Cl H H A46 OCF₃ Cl H H A47 OCHF₂ Cl H H A48 OCH₂—CF₃ ClH H A49 Phenyl Cl H H A50 Phenoxy Cl H H A51 Benzyl Cl H H A52 Cl Cl H HA53 Br Cl H H A54 I Cl H H A55 NH₂ Cl H H A56 NH-Phenyl Cl H H A57 CN ClH H A58 NH-Benzyl Cl H H A59 4-cyanophenyl Cl H H A60 1,4-oxazepan-4-ylCl H H A61 4-Morpholinyl Cl H H A62 4-Methylpiperazin-1-yl Cl H H A63N(2-methoxyethyl)(methyl) Cl H H A64 N(3-methoxypropyl)(methyl) Cl H HA65 H H Cl H A66 CH₃ H Cl H A67 C₂H₅ H Cl H A68 n-C₃H₇ H Cl H A69 n-C₄H₉H Cl H A70 n-C₅H₁₁ H Cl H A71 n-C₆H₁₃ H Cl H A72 CF₃ H Cl H A73 CH₂CF₃ HCl H A74 OCH₃ H Cl H A75 OCH₂—CH₃ H Cl H A76 OCH₂—CH₂—CH₃ H Cl H A77OCH₂—CH₂—CH₂—CH₃ H Cl H A78 OCF₃ H Cl H A79 OCHF₂ H Cl H A80 OCH₂—CF₃ HCl H A81 Phenyl H Cl H A82 Phenoxy H Cl H A83 Benzyl H Cl H A84 Cl H ClH A85 Br H Cl H A86 I H Cl H A87 NH₂ H Cl H A88 NH-Phenyl H Cl H A89 CNH Cl H A90 NH-Benzyl H Cl H A91 4-cyanophenyl H Cl H A921,4-oxazepan-4-yl H Cl H A93 4-Morpholinyl H Cl H A944-Methylpiperazin-1-yl H Cl H A95 N(2-methoxyethyl)(methyl) H Cl H A96N(3-methoxypropyl)(methyl) H Cl H A97 H Br H H A98 CH₃ Br H H A99 C₂H₅Br H H A100 n-C₃H₇ Br H H A101 n-C₄H₉ Br H H A102 n-C₅H₁₁ Br H H A103n-C₆H₁₃ Br H H A104 CF₃ Br H H A105 CH₂CF₃ Br H H A106 OCH₃ Br H H A107OCH₂—CH₃ Br H H A108 OCH₂—CH₂—CH₃ Br H H A109 OCH₂—CH₂—CH₂—CH₃ Br H HA110 OCF₃ Br H H A111 OCHF₂ Br H H A112 OCH₂—CF₃ Br H H A113 Phenyl Br HH A114 Phenoxy Br H H A115 Benzyl Br H H A116 Cl Br H H A117 Br Br H HA118 I Br H H A119 NH₂ Br H H A120 NH-Phenyl Br H H A121 CN Br H H A122NH-Benzyl Br H H A123 4-cyanophenyl Br H H A124 1,4-oxazepan-4-yl Br H HA125 4-Morpholinyl Br H H A126 4-Methylpiperazin-1-yl Br H H A127N(2-methoxyethyl)(methyl) Br H H A128 N(3-methoxypropyl)(methyl) Br H HA129 H H Br H A130 CH₃ H Br H A131 C₂H₅ H Br H A132 n-C₃H₇ H Br H A133n-C₄H₉ H Br H A134 n-C₅H₁₁ H Br H A135 n-C₆H₁₃ H Br H A136 CF₃ H Br HA137 CH₂CF₃ H Br H A138 OCH₃ H Br H A139 OCH₂—CH₃ H Br H A140OCH₂—CH₂—CH₃ H Br H A141 OCH₂—CH₂—CH₂—CH₃ H Br H A142 OCF₃ H Br H A143OCHF₂ H Br H A144 OCH₂—CF₃ H Br H A145 Phenyl H Br H A146 Phenoxy H Br HA147 Benzyl H Br H A148 Cl H Br H A149 Br H Br H A150 I H Br H A151 NH₂H Br H A152 NH-Phenyl H Br H A153 CN H Br H A154 NH-Benzyl H Br H A1554-cyanophenyl H Br H A156 1,4-oxazepan-4-yl H Br H A157 4-Morpholinyl HBr H A158 4-Methylpiperazin-1-yl H Br H A159 N(2-methoxyethyl)(methyl) HBr H A160 N(3-methoxypropyl)(methyl) H Br H A161 H CH₃ H H A162 CH₃ CH₃H H A163 C₂H₅ CH₃ H H A164 n-C₃H₇ CH₃ H H A165 n-C₄H₉ CH₃ H H A166n-C₅H₁₁ CH₃ H H A167 n-C₆H₁₃ CH₃ H H A168 CF₃ CH₃ H H A169 CH₂CF₃ CH₃ HH A170 OCH₃ CH₃ H H A171 OCH₂—CH₃ CH₃ H H A172 OCH₂—CH₂—CH₃ CH₃ H H A173OCH₂—CH₂—CH₂—CH₃ CH₃ H H A174 OCF₃ CH₃ H H A175 OCHF₂ CH₃ H H A176OCH₂—CF₃ CH₃ H H A177 Phenyl CH₃ H H A178 Phenoxy CH₃ H H A179 BenzylCH₃ H H A180 Cl CH₃ H H A181 Br CH₃ H H A182 I CH₃ H H A183 NH₂ CH₃ H HA184 NH-Phenyl CH₃ H H A185 CN CH₃ H H A186 NH-Benzyl CH₃ H H A1874-cyanophenyl CH₃ H H A188 1,4-oxazepan-4-yl CH₃ H H A189 4-MorpholinylCH₃ H H A190 4-Methylpiperazin-1-yl CH₃ H H A191N(2-methoxyethyl)(methyl) CH₃ H H A192 N(3-methoxypropyl)(methyl) CH₃ HH A193 H H CH₃ H A194 CH₃ H CH₃ H A195 C₂H₅ H CH₃ H A196 n-C₃H₇ H CH₃ HA197 n-C₄H₉ H CH₃ H A198 n-C₅H₁₁ H CH₃ H A199 n-C₆H₁₃ H CH₃ H A200 CF₃ HCH₃ H A201 CH₂CF₃ H CH₃ H A202 OCH₃ H CH₃ H A203 OCH₂—CH₃ H CH₃ H A204OCH₂—CH₂—CH₃ H CH₃ H A205 OCH₂—CH₂—CH₂—CH₃ H CH₃ H A206 OCF₃ H CH₃ HA207 OCHF₂ H CH₃ H A208 OCH₂—CF₃ H CH₃ H A209 Phenyl H CH₃ H A210Phenoxy H CH₃ H A211 Benzyl H CH₃ H A212 Cl H CH₃ H A213 Br H CH₃ H A214I H CH₃ H A215 NH₂ H CH₃ H A216 NH-Phenyl H CH₃ H A217 CN H CH₃ H A218NH-Benzyl H CH₃ H A219 4-cyanophenyl H CH₃ H A220 1,4-oxazepan-4-yl HCH₃ H A221 4-Morpholinyl H CH₃ H A222 4-Methylpiperazin-1-yl H CH₃ HA223 N(2-methoxyethyl)(methyl) H CH₃ H A224 N(3-methoxypropyl)(methyl) HCH₃ H A225 H CH₃ CH₃ H A226 CH₃ CH₃ CH₃ H A227 C₂H₅ CH₃ CH₃ H A228n-C₃H₇ CH₃ CH₃ H A229 n-C₄H₉ CH₃ CH₃ H A230 n-C₅H₁₁ CH₃ CH₃ H A231n-C₆H₁₃ CH₃ CH₃ H A232 CF₃ CH₃ CH₃ H A233 CH₂CF₃ CH₃ CH₃ H A234 OCH₃ CH₃CH₃ H A235 OCH₂—CH₃ CH₃ CH₃ H A236 OCH₂—CH₂—CH₃ CH₃ CH₃ H A237OCH₂—CH₂—CH₂—CH₃ CH₃ CH₃ H A238 OCF₃ CH₃ CH₃ H A239 OCHF₂ CH₃ CH₃ H A240OCH₂—CF₃ CH₃ CH₃ H A241 Phenyl CH₃ CH₃ H A242 Phenoxy CH₃ CH₃ H A243Benzyl CH₃ CH₃ H A244 Cl CH₃ CH₃ H A245 Br CH₃ CH₃ H A246 I CH₃ CH₃ HA247 NH₂ CH₃ CH₃ H A248 NH-Phenyl CH₃ CH₃ H A249 CN CH₃ CH₃ H A250NH-Benzyl CH₃ CH₃ H A251 4-cyanophenyl CH₃ CH₃ H A252 1,4-oxazepan-4-ylCH₃ CH₃ H A253 4-Morpholinyl CH₃ CH₃ H A254 4-Methylpiperazin-1-yl CH₃CH₃ H A255 N(2-methoxyethyl)(methyl) CH₃ CH₃ H A256N(3-methoxypropyl)(methyl) CH₃ CH₃ H A257 H C₂H₅ C₂H₅ H A258 CH₃ C₂H₅C₂H₅ H A259 C₂H₅ C₂H₅ C₂H₅ H A260 n-C₃H₇ C₂H₅ C₂H₅ H A261 n-C₄H₉ C₂H₅C₂H₅ H A262 n-C₅H₁₁ C₂H₅ C₂H₅ H A263 n-C₆H₁₃ C₂H₅ C₂H₅ H A264 CF₃ C₂H₅C₂H₅ H A265 CH₂CF₃ C₂H₅ C₂H₅ H A266 OCH₃ C₂H₅ C₂H₅ H A267 OCH₂—CH₃ C₂H₅C₂H₅ H A268 OCH₂—CH₂—CH₃ C₂H₅ C₂H₅ H A269 OCH₂—CH₂—CH₂—CH₃ C₂H₅ C₂H₅ HA270 OCF₃ C₂H₅ C₂H₅ H A271 OCHF₂ C₂H₅ C₂H₅ H A272 OCH₂—CF₃ C₂H₅ C₂H₅ HA273 Phenyl C₂H₅ C₂H₅ H A274 Phenoxy C₂H₅ C₂H₅ H A275 Benzyl C₂H₅ C₂H₅ HA276 Cl C₂H₅ C₂H₅ H A277 Br C₂H₅ C₂H₅ H A278 I C₂H₅ C₂H₅ H A279 NH₂ C₂H₅C₂H₅ H A280 NH-Phenyl C₂H₅ C₂H₅ H A281 CN C₂H₅ C₂H₅ H A282 NH-BenzylC₂H₅ C₂H₅ H A283 4-cyanophenyl C₂H₅ C₂H₅ H A284 1,4-oxazepan-4-yl C₂H₅C₂H₅ H A285 4-Morpholinyl C₂H₅ C₂H₅ H A286 4-Methylpiperazin-1-yl C₂H₅C₂H₅ H A287 N(2-methoxyethyl)(methyl) C₂H₅ C₂H₅ H A288N(3-methoxypropyl)(methyl) C₂H₅ C₂H₅ H A289 H CH₃O H H A290 CH₃ CH₃O H HA291 C₂H₅ CH₃O H H A292 n-C₃H₇ CH₃O H H A293 n-C₄H₉ CH₃O H H A294n-C₅H₁₁ CH₃O H H A295 n-C₆H₁₃ CH₃O H H A296 CF₃ CH₃O H H A297 CH₂CF₃CH₃O H H A298 OCH₃ CH₃O H H A299 OCH₂—CH₃ CH₃O H H A300 OCH₂—CH₂—CH₃CH₃O H H A301 OCH₂—CH₂—CH₂—CH₃ CH₃O H H A302 OCF₃ CH₃O H H A303 OCHF₂CH₃O H H A304 OCH₂—CF₃ CH₃O H H A305 Phenyl CH₃O H H A306 Phenoxy CH₃O HH A307 Benzyl CH₃O H H A308 Cl CH₃O H H A309 Br CH₃O H H A310 I CH₃O H HA311 NH₂ CH₃O H H A312 NH-Phenyl CH₃O H H A313 CN CH₃O H H A314NH-Benzyl CH₃O H H A315 4-cyanophenyl CH₃O H H A316 1,4-oxazepan-4-ylCH₃O H H A317 4-Morpholinyl CH₃O H H A318 4-Methylpiperazin-1-yl CH₃O HH A319 N(2-methoxyethyl)(methyl) CH₃O H H A320N(3-methoxypropyl)(methyl) CH₃O H H A321 H H CH₃O H A322 CH₃ H CH₃O HA323 C₂H₅ H CH₃O H A324 n-C₃H₇ H CH₃O H A325 n-C₄H₉ H CH₃O H A326n-C₅H₁₁ H CH₃O H A327 n-C₆H₁₃ H CH₃O H A328 CF₃ H CH₃O H A329 CH₂CF₃ HCH₃O H A330 OCH₃ H CH₃O H A331 OCH₂—CH₃ H CH₃O H A332 OCH₂—CH₂—CH₃ HCH₃O H A333 OCH₂—CH₂—CH₂—CH₃ H CH₃O H A334 OCF₃ H CH₃O H A335 OCHF₂ HCH₃O H A336 OCH₂—CF₃ H CH₃O H A337 Phenyl H CH₃O H A338 Phenoxy H CH₃O HA339 Benzyl H CH₃O H A340 Cl H CH₃O H A341 Br H CH₃O H A342 I H CH₃O HA343 NH₂ H CH₃O H A344 NH-Phenyl H CH₃O H A345 CN H CH₃O H A346NH-Benzyl H CH₃O H A347 4-cyanophenyl H CH₃O H A348 1,4-oxazepan-4-yl HCH₃O H A349 4-Morpholinyl H CH₃O H A350 4-Methylpiperazin-1-yl H CH₃O HA351 N(2-methoxyethyl)(methyl) H CH₃O H A352 N(3-methoxypropyl)(methyl)H CH₃O H A353 H H H CH₃ A354 CH₃ H H CH₃ A355 C₂H₅ H H CH₃ A356 n-C₃H₇ HH CH₃ A357 n-C₄H₉ H H CH₃ A358 n-C₅H₁₁ H H CH₃ A359 n-C₆H₁₃ H H CH₃ A360CF₃ H H CH₃ A361 CH₂CF₃ H H CH₃ A362 OCH₃ H H CH₃ A363 OCH₂—CH₃ H H CH₃A364 OCH₂—CH₂—CH₃ H H CH₃ A365 OCH₂—CH₂—CH₂—CH₃ H H CH₃ A366 OCF₃ H HCH₃ A367 OCHF₂ H H CH₃ A368 OCH₂—CF₃ H H CH₃ A369 Phenyl H H CH₃ A370Phenoxy H H CH₃ A371 Benzyl H H CH₃ A372 Cl H H CH₃ A373 Br H H CH₃ A374I H H CH₃ A375 NH₂ H H CH₃ A376 NH-Phenyl H H CH₃ A377 CN H H CH₃ A378NH-Benzyl H H CH₃ A379 4-cyanophenyl H H CH₃ A380 1,4-oxazepan-4-yl H HCH₃ A381 4-Morpholinyl H H CH₃ A382 4-Methylpiperazin-1-yl H H CH₃ A383N(2-methoxyethyl)(methyl) H H CH₃ A384 N(3-methoxypropyl)(methyl) H HCH₃ A385 H Cl H CH₃ A386 CH₃ Cl H CH₃ A387 C₂H₅ Cl H CH₃ A388 n-C₃H₇ ClH CH₃ A389 n-C₄H₉ Cl H CH₃ A390 n-C₅H₁₁ Cl H CH₃ A391 n-C₆H₁₃ Cl H CH₃A392 CF₃ Cl H CH₃ A393 CH₂CF₃ Cl H CH₃ A394 OCH₃ Cl H CH₃ A395 OCH₂—CH₃Cl H CH₃ A396 OCH₂—CH₂—CH₃ Cl H CH₃ A397 OCH₂—CH₂—CH₂—CH₃ Cl H CH₃ A398OCF₃ Cl H CH₃ A399 OCHF₂ Cl H CH₃ A400 OCH₂—CF₃ Cl H CH₃ A401 Phenyl ClH CH₃ A402 Phenoxy Cl H CH₃ A403 Benzyl Cl H CH₃ A404 Cl Cl H CH₃ A405Br Cl H CH₃ A406 I Cl H CH₃ A407 NH₂ Cl H CH₃ A408 NH-Phenyl Cl H CH₃A409 CN Cl H CH₃ A410 NH-Benzyl Cl H CH₃ A411 4-cyanophenyl Cl H CH₃A412 1,4-oxazepan-4-yl Cl H CH₃ A413 4-Morpholinyl Cl H CH₃ A4144-Methylpiperazin-1-yl Cl H CH₃ A415 N(2-methoxyethyl)(methyl) Cl H CH₃A416 N(3-methoxypropyl)(methyl) Cl H CH₃ A417 H H Cl CH₃ A418 CH₃ H ClCH₃ A419 C₂H₅ H Cl CH₃ A420 n-C₃H₇ H Cl CH₃ A421 n-C₄H₉ H Cl CH₃ A422n-C₅H₁₁ H Cl CH₃ A423 n-C₆H₁₃ H Cl CH₃ A424 CF₃ H Cl CH₃ A425 CH₂CF₃ HCl CH₃ A426 OCH₃ H Cl CH₃ A427 OCH₂—CH₃ H Cl CH₃ A428 OCH₂—CH₂—CH₃ H ClCH₃ A429 OCH₂—CH₂—CH₂—CH₃ H Cl CH₃ A430 OCF₃ H Cl CH₃ A431 OCHF₂ H ClCH₃ A432 OCH₂—CF₃ H Cl CH₃ A433 Phenyl H Cl CH₃ A434 Phenoxy H Cl CH₃A435 Benzyl H Cl CH₃ A436 Cl H Cl CH₃ A437 Br H Cl CH₃ A438 I H Cl CH₃A439 NH₂ H Cl CH₃ A440 NH-Phenyl H Cl CH₃ A441 CN H Cl CH₃ A442NH-Benzyl H Cl CH₃ A443 4-cyanophenyl H Cl CH₃ A444 1,4-oxazepan-4-yl HCl CH₃ A445 4-Morpholinyl H Cl CH₃ A446 4-Methylpiperazin-1-yl H Cl CH₃A447 N(2-methoxyethyl)(methyl) H Cl CH₃ A448 N(3-methoxypropyl)(methyl)H Cl CH₃ A449 H Br H CH₃ A450 CH₃ Br H CH₃ A451 C₂H₅ Br H CH₃ A452n-C₃H₇ Br H CH₃ A453 n-C₄H₉ Br H CH₃ A454 n-C₅H₁₁ Br H CH₃ A455 n-C₆H₁₃Br H CH₃ A456 CF₃ Br H CH₃ A457 CH₂CF₃ Br H CH₃ A458 OCH₃ Br H CH₃ A459OCH₂—CH₃ Br H CH₃ A460 OCH₂—CH₂—CH₃ Br H CH₃ A461 OCH₂—CH₂—CH₂—CH₃ Br HCH₃ A462 OCF₃ Br H CH₃ A463 OCHF₂ Br H CH₃ A464 OCH₂—CF₃ Br H CH₃ A465Phenyl Br H CH₃ A466 Phenoxy Br H CH₃ A467 Benzyl Br H CH₃ A468 Cl Br HCH₃ A469 Br Br H CH₃ A470 I Br H CH₃ A471 NH₂ Br H CH₃ A472 NH-Phenyl BrH CH₃ A473 CN Br H CH₃ A474 NH-Benzyl Br H CH₃ A475 4-cyanophenyl Br HCH₃ A476 1,4-oxazepan-4-yl Br H CH₃ A477 4-Morpholinyl Br H CH₃ A4784-Methylpiperazin-1-yl Br H CH₃ A479 N(2-methoxyethyl)(methyl) Br H CH₃A480 N(3-methoxypropyl)(methyl) Br H CH₃ A481 H H Br CH₃ A482 CH₃ H BrCH₃ A483 C₂H₅ H Br CH₃ A484 n-C₃H₇ H Br CH₃ A485 n-C₄H₉ H Br CH₃ A486n-C₅H₁₁ H Br CH₃ A487 n-C₆H₁₃ H Br CH₃ A488 CF₃ H Br CH₃ A489 CH₂CF₃ HBr CH₃ A490 OCH₃ H Br CH₃ A491 OCH₂—CH₃ H Br CH₃ A492 OCH₂—CH₂—CH₃ H BrCH₃ A493 OCH₂—CH₂—CH₂—CH₃ H Br CH₃ A494 OCF₃ H Br CH₃ A495 OCHF₂ H BrCH₃ A496 OCH₂—CF₃ H Br CH₃ A497 Phenyl H Br CH₃ A498 Phenoxy H Br CH₃A499 Benzyl H Br CH₃ A500 Cl H Br CH₃ A501 Br H Br CH₃ A502 I H Br CH₃A503 NH₂ H Br CH₃ A504 NH-Phenyl H Br CH₃ A505 CN H Br CH₃ A506NH-Benzyl H Br CH₃ A507 4-cyanophenyl H Br CH₃ A508 1,4-oxazepan-4-yl HBr CH₃ A509 4-Morpholinyl H Br CH₃ A510 4-Methylpiperazin-1-yl H Br CH₃A511 N(2-methoxyethyl)(methyl) H Br CH₃ A512 N(3-methoxypropyl)(methyl)H Br CH₃ A513 H CH₃ H CH₃ A514 CH₃ CH₃ H CH₃ A515 C₂H₅ CH₃ H CH₃ A516n-C₃H₇ CH₃ H CH₃ A517 n-C₄H₉ CH₃ H CH₃ A518 n-C₅H₁₁ CH₃ H CH₃ A519n-C₆H₁₃ CH₃ H CH₃ A520 CF₃ CH₃ H CH₃ A521 CH₂CF₃ CH₃ H CH₃ A522 OCH₃ CH₃H CH₃ A523 OCH₂—CH₃ CH₃ H CH₃ A524 OCH₂—CH₂—CH₃ CH₃ H CH₃ A525OCH₂—CH₂—CH₂—CH₃ CH₃ H CH₃ A526 OCF₃ CH₃ H CH₃ A527 OCHF₂ CH₃ H CH₃ A528OCH₂—CF₃ CH₃ H CH₃ A529 Phenyl CH₃ H CH₃ A530 Phenoxy CH₃ H CH₃ A531Benzyl CH₃ H CH₃ A532 Cl CH₃ H CH₃ A533 Br CH₃ H CH₃ A534 I CH₃ H CH₃A535 NH₂ CH₃ H CH₃ A536 NH-Phenyl CH₃ H CH₃ A537 CN CH₃ H CH₃ A538NH-Benzyl CH₃ H CH₃ A539 4-cyanophenyl CH₃ H CH₃ A540 1,4-oxazepan-4-ylCH₃ H CH₃ A541 4-Morpholinyl CH₃ H CH₃ A542 4-Methylpiperazin-1-yl CH₃ HCH₃ A543 N(2-methoxyethyl)(methyl) CH₃ H CH₃ A544N(3-methoxypropyl)(methyl) CH₃ H CH₃ A545 H H CH₃ CH₃ A546 CH₃ H CH₃ CH₃A547 C₂H₅ H CH₃ CH₃ A548 n-C₃H₇ H CH₃ CH₃ A549 n-C₄H₉ H CH₃ CH₃ A550n-C₅H₁₁ H CH₃ CH₃ A551 n-C₆H₁₃ H CH₃ CH₃ A552 CF₃ H CH₃ CH₃ A553 CH₂CF₃H CH₃ CH₃ A554 OCH₃ H CH₃ CH₃ A555 OCH₂—CH₃ H CH₃ CH₃ A556 OCH₂—CH₂—CH₃H CH₃ CH₃ A557 OCH₂—CH₂—CH₂—CH₃ H CH₃ CH₃ A558 OCF₃ H CH₃ CH₃ A559 OCHF₂H CH₃ CH₃ A560 OCH₂—CF₃ H CH₃ CH₃ A561 Phenyl H CH₃ CH₃ A562 Phenoxy HCH₃ CH₃ A563 Benzyl H CH₃ CH₃ A564 Cl H CH₃ CH₃ A565 Br H CH₃ CH₃ A566 IH CH₃ CH₃ A567 NH₂ H CH₃ CH₃ A568 NH-Phenyl H CH₃ CH₃ A569 CN H CH₃ CH₃A570 NH-Benzyl H CH₃ CH₃ A571 4-cyanophenyl H CH₃ CH₃ A5721,4-oxazepan-4-yl H CH₃ CH₃ A573 4-Morpholinyl H CH₃ CH₃ A5744-Methylpiperazin-1-yl H CH₃ CH₃ A575 N(2-methoxyethyl)(methyl) H CH₃CH₃ A576 N(3-methoxypropyl)(methyl) H CH₃ CH₃ A577 H CH₃ CH₃ CH₃ A578CH₃ CH₃ CH₃ CH₃ A579 C₂H₅ CH₃ CH₃ CH₃ A580 n-C₃H₇ CH₃ CH₃ CH₃ A581n-C₄H₉ CH₃ CH₃ CH₃ A582 n-C₅H₁₁ CH₃ CH₃ CH₃ A583 n-C₆H₁₃ CH₃ CH₃ CH₃A584 CF₃ CH₃ CH₃ CH₃ A585 CH₂CF₃ CH₃ CH₃ CH₃ A586 OCH₃ CH₃ CH₃ CH₃ A587OCH₂—CH₃ CH₃ CH₃ CH₃ A588 OCH₂—CH₂—CH₃ CH₃ CH₃ CH₃ A589 OCH₂—CH₂—CH₂—CH₃CH₃ CH₃ CH₃ A590 OCF₃ CH₃ CH₃ CH₃ A591 OCHF₂ CH₃ CH₃ CH₃ A592 OCH₂—CF₃CH₃ CH₃ CH₃ A593 Phenyl CH₃ CH₃ CH₃ A594 Phenoxy CH₃ CH₃ CH₃ A595 BenzylCH₃ CH₃ CH₃ A596 Cl CH₃ CH₃ CH₃ A597 Br CH₃ CH₃ CH₃ A598 I CH₃ CH₃ CH₃A599 NH₂ CH₃ CH₃ CH₃ A600 NH-Phenyl CH₃ CH₃ CH₃ A601 CN CH₃ CH₃ CH₃ A602NH-Benzyl CH₃ CH₃ CH₃ A603 4-cyanophenyl CH₃ CH₃ CH₃ A6041,4-oxazepan-4-yl CH₃ CH₃ CH₃ A605 4-Morpholinyl CH₃ CH₃ CH₃ A6064-Methylpiperazin-1-yl CH₃ CH₃ CH₃ A607 N(2-methoxyethyl)(methyl) CH₃CH₃ CH₃ A608 N(3-methoxypropyl)(methyl) CH₃ CH₃ CH₃ A609 H C₂H₅ C₂H₅ CH₃A610 CH₃ C₂H₅ C₂H₅ CH₃ A611 C₂H₅ C₂H₅ C₂H₅ CH₃ A612 n-C₃H₇ C₂H₅ C₂H₅ CH₃A613 n-C₄H₉ C₂H₅ C₂H₅ CH₃ A614 n-C₅H₁₁ C₂H₅ C₂H₅ CH₃ A615 n-C₆H₁₃ C₂H₅C₂H₅ CH₃ A616 CF₃ C₂H₅ C₂H₅ CH₃ A617 CH₂CF₃ C₂H₅ C₂H₅ CH₃ A618 OCH₃ C₂H₅C₂H₅ CH₃ A619 OCH₂—CH₃ C₂H₅ C₂H₅ CH₃ A620 OCH₂—CH₂—CH₃ C₂H₅ C₂H₅ CH₃A621 OCH₂—CH₂—CH₂—CH₃ C₂H₅ C₂H₅ CH₃ A622 OCF₃ C₂H₅ C₂H₅ CH₃ A623 OCHF₂C₂H₅ C₂H₅ CH₃ A624 OCH₂—CF₃ C₂H₅ C₂H₅ CH₃ A625 Phenyl C₂H₅ C₂H₅ CH₃ A626Phenoxy C₂H₅ C₂H₅ CH₃ A627 Benzyl C₂H₅ C₂H₅ CH₃ A628 Cl C₂H₅ C₂H₅ CH₃A629 Br C₂H₅ C₂H₅ CH₃ A630 I C₂H₅ C₂H₅ CH₃ A631 NH₂ C₂H₅ C₂H₅ CH₃ A632NH-Phenyl C₂H₅ C₂H₅ CH₃ A633 CN C₂H₅ C₂H₅ CH₃ A634 NH-Benzyl C₂H₅ C₂H₅CH₃ A635 4-cyanophenyl C₂H₅ C₂H₅ CH₃ A636 1,4-oxazepan-4-yl C₂H₅ C₂H₅CH₃ A637 4-Morpholinyl C₂H₅ C₂H₅ CH₃ A638 4-Methylpiperazin-1-yl C₂H₅C₂H₅ CH₃ A639 N(2-methoxyethyl)(methyl) C₂H₅ C₂H₅ CH₃ A640N(3-methoxypropyl)(methyl) C₂H₅ C₂H₅ CH₃ A641 H CH₃O H CH₃ A642 CH₃ CH₃OH CH₃ A643 C₂H₅ CH₃O H CH₃ A644 n-C₃H₇ CH₃O H CH₃ A645 n-C₄H₉ CH₃O H CH₃A646 n-C₅H₁₁ CH₃O H CH₃ A647 n-C₆H₁₃ CH₃O H CH₃ A648 CF₃ CH₃O H CH₃ A649CH₂CF₃ CH₃O H CH₃ A650 OCH₃ CH₃O H CH₃ A651 OCH₂—CH₃ CH₃O H CH₃ A652OCH₂—CH₂—CH₃ CH₃O H CH₃ A653 OCH₂—CH₂—CH₂—CH₃ CH₃O H CH₃ A654 OCF₃ CH₃OH CH₃ A655 OCHF₂ CH₃O H CH₃ A656 OCH₂—CF₃ CH₃O H CH₃ A657 Phenyl CH₃O HCH₃ A658 Phenoxy CH₃O H CH₃ A659 Benzyl CH₃O H CH₃ A660 Cl CH₃O H CH₃A661 Br CH₃O H CH₃ A662 I CH₃O H CH₃ A663 NH₂ CH₃O H CH₃ A664 NH-PhenylCH₃O H CH₃ A665 CN CH₃O H CH₃ A666 NH-Benzyl CH₃O H CH₃ A6674-cyanophenyl CH₃O H CH₃ A668 1,4-oxazepan-4-yl CH₃O H CH₃ A6694-Morpholinyl CH₃O H CH₃ A670 4-Methylpiperazin-1-yl CH₃O H CH₃ A671N(2-methoxyethyl)(methyl) CH₃O H CH₃ A672 N(3-methoxypropyl)(methyl)CH₃O H CH₃ A673 H H CH₃O CH₃ A674 CH₃ H CH₃O CH₃ A675 C₂H₅ H CH₃O CH₃A676 n-C₃H₇ H CH₃O CH₃ A677 n-C₄H₉ H CH₃O CH₃ A678 n-C₅H₁₁ H CH₃O CH₃A679 n-C₆H₁₃ H CH₃O CH₃ A680 CF₃ H CH₃O CH₃ A681 CH₂CF₃ H CH₃O CH₃ A682OCH₃ H CH₃O CH₃ A683 OCH₂—CH₃ H CH₃O CH₃ A684 OCH₂—CH₂—CH₃ H CH₃O CH₃A685 OCH₂—CH₂—CH₂—CH₃ H CH₃O CH₃ A686 OCF₃ H CH₃O CH₃ A687 OCHF₂ H CH₃OCH₃ A688 OCH₂—CF₃ H CH₃O CH₃ A689 Phenyl H CH₃O CH₃ A690 Phenoxy H CH₃OCH₃ A691 Benzyl H CH₃O CH₃ A692 Cl H CH₃O CH₃ A693 Br H CH₃O CH₃ A694 IH CH₃O CH₃ A695 NH₂ H CH₃O CH₃ A696 NH-Phenyl H CH₃O CH₃ A697 CN H CH₃OCH₃ A698 NH-Benzyl H CH₃O CH₃ A699 4-cyanophenyl H CH₃O CH₃ A7001,4-oxazepan-4-yl H CH₃O CH₃ A701 4-Morpholinyl H CH₃O CH₃ A7024-Methylpiperazin-1-yl H CH₃O CH₃ A703 N(2-methoxyethyl)(methyl) H CH₃OCH₃ A704 N(3-methoxypropyl)(methyl) H CH₃O CH₃ A705 H H H Cl A706 CH₃ HH Cl A707 C₂H₅ H H Cl A708 n-C₃H₇ H H Cl A709 n-C₄H₉ H H Cl A710 n-C₅H₁₁H H Cl A711 n-C₆H₁₃ H H Cl A712 CF₃ H H Cl A713 CH₂CF₃ H H Cl A714 OCH₃H H Cl A715 OCH₂—CH₃ H H Cl A716 OCH₂—CH₂—CH₃ H H Cl A717OCH₂—CH₂—CH₂—CH₃ H H Cl A718 OCF₃ H H Cl A719 OCHF₂ H H Cl A720 OCH₂—CF₃H H Cl A721 Phenyl H H Cl A722 Phenoxy H H Cl A723 Benzyl H H Cl A724 ClH H Cl A725 Br H H Cl A726 I H H Cl A727 NH₂ H H Cl A728 NH-Phenyl H HCl A729 CN H H Cl A730 NH-Benzyl H H Cl A731 4-cyanophenyl H H Cl A7321,4-oxazepan-4-yl H H Cl A733 4-Morpholinyl H H Cl A7344-Methylpiperazin-1-yl H H Cl A735 N(2-methoxyethyl)(methyl) H H Cl A736N(3-methoxypropyl)(methyl) H H Cl A737 H Cl H Cl A738 CH₃ Cl H Cl A739C₂H₅ Cl H Cl A740 n-C₃H₇ Cl H Cl A741 n-C₄H₉ Cl H Cl A742 n-C₅H₁₁ Cl HCl A743 n-C₆H₁₃ Cl H Cl A744 CF₃ Cl H Cl A745 CH₂CF₃ Cl H Cl A746 OCH₃Cl H Cl A747 OCH₂—CH₃ Cl H Cl A748 OCH₂—CH₂—CH₃ Cl H Cl A749OCH₂—CH₂—CH₂—CH₃ Cl H Cl A750 OCF₃ Cl H Cl A751 OCHF₂ Cl H Cl A752OCH₂—CF₃ Cl H Cl A753 Phenyl Cl H Cl A754 Phenoxy Cl H Cl A755 Benzyl ClH Cl A756 Cl Cl H Cl A757 Br Cl H Cl A758 I Cl H Cl A759 NH₂ Cl H ClA760 NH-Phenyl Cl H Cl A761 CN Cl H Cl A762 NH-Benzyl Cl H Cl A7634-cyanophenyl Cl H Cl A764 1,4-oxazepan-4-yl Cl H Cl A765 4-MorpholinylCl H Cl A766 4-Methylpiperazin-1-yl Cl H Cl A767N(2-methoxyethyl)(methyl) Cl H Cl A768 N(3-methoxypropyl)(methyl) Cl HCl A769 H H Cl Cl A770 CH₃ H Cl Cl A771 C₂H₅ H Cl Cl A772 n-C₃H₇ H Cl ClA773 n-C₄H₉ H Cl Cl A774 n-C₅H₁₁ H Cl Cl A775 n-C₆H₁₃ H Cl Cl A776 CF₃ HCl Cl A777 CH₂CF₃ H Cl Cl A778 OCH₃ H Cl Cl A779 OCH₂—CH₃ H Cl Cl A780OCH₂—CH₂—CH₃ H Cl Cl A781 OCH₂—CH₂—CH₂—CH₃ H Cl Cl A782 OCF₃ H Cl ClA783 OCHF₂ H Cl Cl A784 OCH₂—CF₃ H Cl Cl A785 Phenyl H Cl Cl A786Phenoxy H Cl Cl A787 Benzyl H Cl Cl A788 Cl H Cl Cl A789 Br H Cl Cl A790I H Cl Cl A791 NH₂ H Cl Cl A792 NH-Phenyl H Cl Cl A793 CN H Cl Cl A794NH-Benzyl H Cl Cl A795 4-cyanophenyl H Cl Cl A796 1,4-oxazepan-4-yl H ClCl A797 4-Morpholinyl H Cl Cl A798 4-Methylpiperazin-1-yl H Cl Cl A799N(2-methoxyethyl)(methyl) H Cl Cl A800 N(3-methoxypropyl)(methyl) H ClCl A801 H Br H Cl A802 CH₃ Br H Cl A803 C₂H₅ Br H Cl A804 n-C₃H₇ Br H ClA805 n-C₄H₉ Br H Cl A806 n-C₅H₁₁ Br H Cl A807 n-C₆H₁₃ Br H Cl A808 CF₃Br H Cl A809 CH₂CF₃ Br H Cl A810 OCH₃ Br H Cl A811 OCH₂—CH₃ Br H Cl A812OCH₂—CH₂—CH₃ Br H Cl A813 OCH₂—CH₂—CH₂—CH₃ Br H Cl A814 OCF₃ Br H ClA815 OCHF₂ Br H Cl A816 OCH₂—CF₃ Br H Cl A817 Phenyl Br H Cl A818Phenoxy Br H Cl A819 Benzyl Br H Cl A820 Cl Br H Cl A821 Br Br H Cl A822I Br H Cl A823 NH₂ Br H Cl A824 NH-Phenyl Br H Cl A825 CN Br H Cl A826NH-Benzyl Br H Cl A827 4-cyanophenyl Br H Cl A828 1,4-oxazepan-4-yl Br HCl A829 4-Morpholinyl Br H Cl A830 4-Methylpiperazin-1-yl Br H Cl A831N(2-methoxyethyl)(methyl) Br H Cl A832 N(3-methoxypropyl)(methyl) Br HCl A833 H H Br Cl A834 CH₃ H Br Cl A835 C₂H₅ H Br Cl A836 n-C₃H₇ H Br ClA837 n-C₄H₉ H Br Cl A838 n-C₅H₁₁ H Br Cl A839 n-C₆H₁₃ H Br Cl A840 CF₃ HBr Cl A841 CH₂CF₃ H Br Cl A842 OCH₃ H Br Cl A843 OCH₂—CH₃ H Br Cl A844OCH₂—CH₂—CH₃ H Br Cl A845 OCH₂—CH₂—CH₂—CH₃ H Br Cl A846 OCF₃ H Br ClA847 OCHF₂ H Br Cl A848 OCH₂—CF₃ H Br Cl A849 Phenyl H Br Cl A850Phenoxy H Br Cl A851 Benzyl H Br Cl A852 Cl H Br Cl A853 Br H Br Cl A854I H Br Cl A855 NH₂ H Br Cl A856 NH-Phenyl H Br Cl A857 CN H Br Cl A858NH-Benzyl H Br Cl A859 4-cyanophenyl H Br Cl A860 1,4-oxazepan-4-yl H BrCl A861 4-Morpholinyl H Br Cl A862 4-Methylpiperazin-1-yl H Br Cl A863N(2-methoxyethyl)(methyl) H Br Cl A864 N(3-methoxypropyl)(methyl) H BrCl A865 H CH₃ H Cl A866 CH₃ CH₃ H Cl A867 C₂H₅ CH₃ H Cl A868 n-C₃H₇ CH₃H Cl A869 n-C₄H₉ CH₃ H Cl A870 n-C₅H₁₁ CH₃ H Cl A871 n-C₆H₁₃ CH₃ H ClA872 CF₃ CH₃ H Cl A873 CH₂CF₃ CH₃ H Cl A874 OCH₃ CH₃ H Cl A875 OCH₂—CH₃CH₃ H Cl A876 OCH₂—CH₂—CH₃ CH₃ H Cl A877 OCH₂—CH₂—CH₂—CH₃ CH₃ H Cl A878OCF₃ CH₃ H Cl A879 OCHF₂ CH₃ H Cl A880 OCH₂—CF₃ CH₃ H Cl A881 Phenyl CH₃H Cl A882 Phenoxy CH₃ H Cl A883 Benzyl CH₃ H Cl A884 Cl CH₃ H Cl A885 BrCH₃ H Cl A886 I CH₃ H Cl A887 NH₂ CH₃ H Cl A888 NH-Phenyl CH₃ H Cl A889CN CH₃ H Cl A890 NH-Benzyl CH₃ H Cl A891 4-cyanophenyl CH₃ H Cl A8921,4-oxazepan-4-yl CH₃ H Cl A893 4-Morpholinyl CH₃ H Cl A8944-Methylpiperazin-1-yl CH₃ H Cl A895 N(2-methoxyethyl)(methyl) CH₃ H ClA896 N(3-methoxypropyl)(methyl) CH₃ H Cl A897 H H CH₃ Cl A898 CH₃ H CH₃Cl A899 C₂H₅ H CH₃ Cl A900 n-C₃H₇ H CH₃ Cl A901 n-C₄H₉ H CH₃ Cl A902n-C₅H₁₁ H CH₃ Cl A903 n-C₆H₁₃ H CH₃ Cl A904 CF₃ H CH₃ Cl A905 CH₂CF₃ HCH₃ Cl A906 OCH₃ H CH₃ Cl A907 OCH₂—CH₃ H CH₃ Cl A908 OCH₂—CH₂—CH₃ H CH₃Cl A909 OCH₂—CH₂—CH₂—CH₃ H CH₃ Cl A910 OCF₃ H CH₃ Cl A911 OCHF₂ H CH₃ ClA912 OCH₂—CF₃ H CH₃ Cl A913 Phenyl H CH₃ Cl A914 Phenoxy H CH₃ Cl A915Benzyl H CH₃ Cl A916 Cl H CH₃ Cl A917 Br H CH₃ Cl A918 I H CH₃ Cl A919NH₂ H CH₃ Cl A920 NH-Phenyl H CH₃ Cl A921 CN H CH₃ Cl A922 NH-Benzyl HCH₃ Cl A923 4-cyanophenyl H CH₃ Cl A924 1,4-oxazepan-4-yl H CH₃ Cl A9254-Morpholinyl H CH₃ Cl A926 4-Methylpiperazin-1-yl H CH₃ Cl A927N(2-methoxyethyl)(methyl) H CH₃ Cl A928 N(3-methoxypropyl)(methyl) H CH₃Cl A929 H CH₃ CH₃ Cl A930 CH₃ CH₃ CH₃ Cl A931 C₂H₅ CH₃ CH₃ Cl A932n-C₃H₇ CH₃ CH₃ Cl A933 n-C₄H₉ CH₃ CH₃ Cl A934 n-C₅H₁₁ CH₃ CH₃ Cl A935n-C₆H₁₃ CH₃ CH₃ Cl A936 CF₃ CH₃ CH₃ Cl A937 CH₂CF₃ CH₃ CH₃ Cl A938 OCH₃CH₃ CH₃ Cl A939 OCH₂—CH₃ CH₃ CH₃ Cl A940 OCH₂—CH₂—CH₃ CH₃ CH₃ Cl A941OCH₂—CH₂—CH₂—CH₃ CH₃ CH₃ Cl A942 OCF₃ CH₃ CH₃ Cl A943 OCHF₂ CH₃ CH₃ ClA944 OCH₂—CF₃ CH₃ CH₃ Cl A945 Phenyl CH₃ CH₃ Cl A946 Phenoxy CH₃ CH₃ ClA947 Benzyl CH₃ CH₃ Cl A948 Cl CH₃ CH₃ Cl A949 Br CH₃ CH₃ Cl A950 I CH₃CH₃ Cl A951 NH₂ CH₃ CH₃ Cl A952 NH-Phenyl CH₃ CH₃ Cl A953 CN CH₃ CH₃ ClA954 NH-Benzyl CH₃ CH₃ Cl A955 4-cyanophenyl CH₃ CH₃ Cl A9561,4-oxazepan-4-yl CH₃ CH₃ Cl A957 4-Morpholinyl CH₃ CH₃ Cl A9584-Methylpiperazin-1-yl CH₃ CH₃ Cl A959 N(2-methoxyethyl)(methyl) CH₃ CH₃Cl A960 N(3-methoxypropyl)(methyl) CH₃ CH₃ Cl A961 H C₂H₅ C₂H₅ Cl A962CH₃ C₂H₅ C₂H₅ Cl A963 C₂H₅ C₂H₅ C₂H₅ Cl A964 n-C₃H₇ C₂H₅ C₂H₅ Cl A965n-C₄H₉ C₂H₅ C₂H₅ Cl A966 n-C₅H₁₁ C₂H₅ C₂H₅ Cl A967 n-C₆H₁₃ C₂H₅ C₂H₅ ClA968 CF₃ C₂H₅ C₂H₅ Cl A969 CH₂CF₃ C₂H₅ C₂H₅ Cl A970 OCH₃ C₂H₅ C₂H₅ ClA971 OCH₂—CH₃ C₂H₅ C₂H₅ Cl A972 OCH₂—CH₂—CH₃ C₂H₅ C₂H₅ Cl A973OCH₂—CH₂—CH₂—CH₃ C₂H₅ C₂H₅ Cl A974 OCF₃ C₂H₅ C₂H₅ Cl A975 OCHF₂ C₂H₅C₂H₅ Cl A976 OCH₂—CF₃ C₂H₅ C₂H₅ Cl A977 Phenyl C₂H₅ C₂H₅ Cl A978 PhenoxyC₂H₅ C₂H₅ Cl A979 Benzyl C₂H₅ C₂H₅ Cl A980 Cl C₂H₅ C₂H₅ Cl A981 Br C₂H₅C₂H₅ Cl A982 I C₂H₅ C₂H₅ Cl A983 NH₂ C₂H₅ C₂H₅ Cl A984 NH-Phenyl C₂H₅C₂H₅ Cl A985 CN C₂H₅ C₂H₅ Cl A986 NH-Benzyl C₂H₅ C₂H₅ Cl A9874-cyanophenyl C₂H₅ C₂H₅ Cl A988 1,4-oxazepan-4-yl C₂H₅ C₂H₅ Cl A9894-Morpholinyl C₂H₅ C₂H₅ Cl A990 4-Methylpiperazin-1-yl C₂H₅ C₂H₅ Cl A991N(2-methoxyethyl)(methyl) C₂H₅ C₂H₅ Cl A992 N(3-methoxypropyl)(methyl)C₂H₅ C₂H₅ Cl A993 H CH₃O H Cl A994 CH₃ CH₃O H Cl A995 C₂H₅ CH₃O H ClA996 n-C₃H₇ CH₃O H Cl A997 n-C₄H₉ CH₃O H Cl A998 n-C₅H₁₁ CH₃O H Cl A999n-C₆H₁₃ CH₃O H Cl A1000 CF₃ CH₃O H Cl A1001 CH₂CF₃ CH₃O H Cl A1002 OCH₃CH₃O H Cl A1003 OCH₂—CH₃ CH₃O H Cl A1004 OCH₂—CH₂—CH₃ CH₃O H Cl A1005OCH₂—CH₂—CH₂—CH₃ CH₃O H Cl A1006 OCF₃ CH₃O H Cl A1007 OCHF₂ CH₃O H ClA1008 OCH₂—CF₃ CH₃O H Cl A1009 Phenyl CH₃O H Cl A1010 Phenoxy CH₃O H ClA1011 Benzyl CH₃O H Cl A1012 Cl CH₃O H Cl A1013 Br CH₃O H Cl A1014 ICH₃O H Cl A1015 NH₂ CH₃O H Cl A1016 NH-Phenyl CH₃O H Cl A1017 CN CH₃O HCl A1018 NH-Benzyl CH₃O H Cl A1019 4-cyanophenyl CH₃O H Cl A10201,4-oxazepan-4-yl CH₃O H Cl A1021 4-Morpholinyl CH₃O H Cl A10224-Methylpiperazin-1-yl CH₃O H Cl A1023 N(2-methoxyethyl)(methyl) CH₃O HCl A1024 N(3-methoxypropyl)(methyl) CH₃O H Cl A1025 H H CH₃O Cl A1026CH₃ H CH₃O Cl A1027 C₂H₅ H CH₃O Cl A1028 n-C₃H₇ H CH₃O Cl A1029 n-C₄H₉ HCH₃O Cl A1030 n-C₅H₁₁ H CH₃O Cl A1031 n-C₆H₁₃ H CH₃O Cl A1032 CF₃ H CH₃OCl A1033 CH₂CF₃ H CH₃O Cl A1034 OCH₃ H CH₃O Cl A1035 OCH₂—CH₃ H CH₃O ClA1036 OCH₂—CH₂—CH₃ H CH₃O Cl A1037 OCH₂—CH₂—CH₂—CH₃ H CH₃O Cl A1038 OCF₃H CH₃O Cl A1039 OCHF₂ H CH₃O Cl A1040 OCH₂—CF₃ H CH₃O Cl A1041 Phenyl HCH₃O Cl A1042 Phenoxy H CH₃O Cl A1043 Benzyl H CH₃O Cl A1044 Cl H CH₃OCl A1045 Br H CH₃O Cl A1046 I H CH₃O Cl A1047 NH₂ H CH₃O Cl A1048NH-Phenyl H CH₃O Cl A1049 CN H CH₃O Cl A1050 NH-Benzyl H CH₃O Cl A10514-cyanophenyl H CH₃O Cl A1052 1,4-oxazepan-4-yl H CH₃O Cl A10534-Morpholinyl H CH₃O Cl A1054 4-Methylpiperazin-1-yl H CH₃O Cl A1055N(2-methoxyethyl)(methyl) H CH₃O Cl A1056 N(3-methoxypropyl)(methyl) HCH₃O Cl A1057 H Br Cl H A1058 H Cl CH₃O H A1059 H CH₃O Cl H A1060 Cl CH₃Cl H

Most preferred are the following compounds, their N-oxides andpharmaceutical acceptable salts:

-   2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one-   5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)ethyl)isoindolin-1-one-   5-((4-phenoxypyridin-3-yl)methoxy)-2-propylisoindolin-1-one-   2-butyl-5-((2-chloro-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one-   2-butyl-5-((2-chloro-4-iodopyridin-3-yl)methoxy)isoindolin-1-one-   5-(4-Phenyl-pyridin-3-ylmethoxy)-2-propyl-2,3-dihydro-isoindol-1-one-   5-(4-Phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydroisoindol-1-one-   1-[4-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-phenyl]-butan-1-one-   [3-(1-oxo-2-propyl-2,3-dihydro-1H-isoindol-5-yloxymethyl)-pyridin-4-yl]-carbamic    acid tert-butyl ester, trifluoroacetate-   2-Butyl-5-(2,6-dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one-   5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydro-isoindol-1-one,    trifluoroacetate-   5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-ethyl-2,3-dihydro-isoindol-1-one-   2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one-   2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one-   2-butyl-5-((4-phenylpyridin-3-yl)methylamino)isoindolin-1-one-   2-butyl-5-((4-phenoxypyridin-3-yl)methylamino)isoindolin-1-one-   2-butyl-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)methylamino)-isoindolin-1-one-   5-((4-aminopyridin-3-yl)methylamino)-2-butylisoindolin-1-one-   2-butyl-5-((4-(phenylamino)pyridin-3-yl)methylamino)isoindolin-1-one-   4-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)benzonitrile-   2-butyl-5-((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methylamino)-isoindolin-1-one-   2-butyl-5-[(quinolin-3-ylmethyl)amino]-2,3-dihydro-1H-isoindol-1-one    trifluoroacetate-   2-butyl-5-[(pyridin-3-ylmethyl)amino]-2,3-dihydro-1H-isoindol-1-one-   7-chloro-2-cyclopropyl-5-{[(2,6-dimethyl-4-phenylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one-   7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-cyclopropyl-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-({[4-(morpholin-4-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-({[4-(4-methylpiperazin-1-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2,3-dihydro-1H-isoindol-1-one-   2-butyl-7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one-   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one-   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-propyl-2,3-dihydro-1H-isoindol-1-one-   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-ethyl-7-methyl-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-((5-phenylpyridin-3-yl)methylamino)isoindolin-1-one-   5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one-   N-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)pivalamide-   2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)-methyl)-4-phenylpyridine    1-oxide-   2-butyl-5-{[(2-chloro-4-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one-   5-{[(6-bromo-2-chloropyridin-3-yl)methyl]amino}-2-butyl-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-{[(2,4-dichloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-{[(6-chloro-2-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-{[(2-chloro-6-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-{[(2-chloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one-   5-{[(2-chloro-4-(trifluoromethyl)pyridin-3-yl)methyl]amino}-2-(2-methoxyethyl)-7-methyl-2,3-dihydro-1H-isoindol-1-one-   2-butyl-5-{[(2,4-dichloro-6-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one-   5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one-   5-[(4-methoxypyridin-3-yl)methoxy]-2-propyl-2,3-dihydro-1H-isoindol-1-one-   7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-(2,2,2-trifluoroethyl)-2,3-dihydro-isoindol-1-one-   2-butyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one-   7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-propyl-2,3-dihydro-isoindol-1-one-   2-ethyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one-   2-butyl-5-[(2-methyl-4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one-   2-butyl-5-[(4-[1,4]oxazepan-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydroisoindol-1-one-   2-butyl-5-({4-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one-   2-butyl-5-({4-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one-   2-butyl-5-({4-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one-   2-butyl-5-(4-methoxy-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one    and-   2-butyl-5-(4-morpholin-4-yl-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one.

The compounds according to the invention can be obtained by differentroutes. Compounds of formula I are generally preparable by anucleophilic substitution reaction as described in scheme 1.Furthermore, if Z is NH and R^(b) is hydrogen, compounds of formula Iare also accessible by an imin formation with subsequent reductivehydrogenation as described in scheme 2.

In scheme 1 the variables R¹, R^(a), R^(b), Q, X², X³, Y¹, Y², Y³, Y⁴and Z are defined as described above. LG represents a leaving group,which can be replaced by any nucleophilic group. Examples of leavinggroups are halogen; such as bromine or iodine or haloalkyl- orarylsulfonates; such as mesylate, tosylate and triflate. According toscheme 1 the compound II is reacted with compound III to form compoundIV (=I) under the condition of a nucleophilic substitution reaction, seee.g. J. March, Advanced Organic Chemistry, fourth edition,Wiley-Interscience, New York, 1992, page 293 ff. and the literaturecited therein. As it is well known to a person skilled in the art theaddition of a base (auxiliary base) can be beneficial. Examples of basesare NaOH, K₂CO₃, KOH or organic bases like tertiary amines, e.g.triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) or1,5-diazabicyclo[4.3.0]non-5-en (DBN) [J. March, Advanced OrganicChemistry, fourth edition, Wiley-Interscience, New York, 1992, page 293ff.].

Compounds of the formula I and IV, respectively, wherein Z is S(O) orS(O)₂, can be prepared from the compounds of the formula I and IV,respectively, wherein Z is S by standard oxidation methods, as describede.g. in WO 2006/058753.

In scheme 2 the variables R¹, R^(a), Q, X², X³, X⁴, Y¹, Y², Y³ and Y⁴are defined as described above. According to scheme 2 compound V and VIreact to form the imin VII. This imin is reduced to form the compoundVIII. The reduction can be performed with any reducing agent, preferablywith borohydrides, in particular with NaCNBH₄, sodiumtriacetoxyborohydride and NaBH₄. For suitable reaction conditions see J.March, Advanced Organic Chemistry, fourth edition, Wiley-Interscience,New York, 1992, page 898 ff. and the literature cited therein.

The N-oxides may be prepared from the compounds of formula I accordingto conventional oxidation methods, for example by treating saidcompounds with an organic peracid; such as metachloroperbenzoic acid or3-chloroperbenzoic acid [Journal of Medicinal Chemistry 38(11),1892-1903 (1995), WO 03/64572]; or with inorganic oxidizing agents; suchas hydrogen peroxide [cf. Journal of Heterocyclic Chemistry 18 (7),1305-1308 (1981)] or oxone [cf. Journal of the American Chemical Society123(25), 5962-5973 (2001)]. The oxidation may lead to pure mono-N-oxidesor to a mixture of different N-oxides, which can be separated byconventional methods; such as chromatography.

The reactions are usually performed in an organic solvent, includingaprotic organic solvent, e.g. substituted amides, lactams and ureas;such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetramethyl urea, cyclic ethers; such as dioxane, tetrahydrofurane,halogenated hydrocarbons; such as dichloromethane, and mixtures thereofas well as mixtures thereof with C₁-C₆-alkanols and/or water.

The reactions described above will be usually performed at temperaturesranging from −10° C. to 100° C., depending on the reactivity of the usedcompounds.

The utility of the compounds in accordance with the present invention asmodulators of metabotropic glutamate receptor activity, in particularmGlu2 activity, may be demonstrated by methodology known in the art. Thecompounds of the present invention can be tested e.g. by evaluatingintracellular Ca²⁺ concentrations in cells permanently expressing humanmGlu receptor, the rat glutamate transporter rGLAST and the Galpha16subunit of the G-protein complex under standard conditions in afluorometric imaging plate reader (FLIPR, Molecular Devices, Union City,Calif. 94587, USA) by measuring the response of the cells to a testcompound in the absence of presence of glutamate. The FLIPR assay is acommon functional assay to monitor native or recombinant Galphaq-coupledreceptors, and native or recombinant receptors normally linked to otherG-protein signalling cascades, which are coupled to calcium throughco-expression of an alpha subunit of a promiscuous or chimericG-protein. In the assay the increase of intracellular calcium ismeasured through a calcium-dependent fluorescent dye (e.g. Fluo-4 AM) inthe FLIPR instrument.

For the purpose of the present study, a cell line permanently expressinga human mGlu receptor, such as the mGlu2 receptor, the rat glutamatetransporter rGLAST and the GalphaG16 may be generated by transfection asdescribed in the examples. For selection of a suitable cell clone andalso the subsequent measurements, the selected clone the cells will beplated on suitable multiwell plates in a suitable medium (e.g. DMEMGlutamax (GIBCO # 21885-025)/10% dialyzed FCS). Cells may be selected bygentamycin treatment as described in the examples. Cells will then beloaded with a suitable Ca²⁺ sensitive fluorescence dye, e.g. with 2 μMFluo-4 AM (Molecular Probes, F14201). Cells will then be washed with asuitable buffer (e.g. HEPES) and the thus treated plates will bemeasured in a fluorometric imaging plate reader (e.g. FLIPR, MolecularDevices, Union City, Calif. 94587, USA).

The compounds of the present invention were tested in theabove-described FLIPR assay using the selected cell clone. Increasedintracellular calcium levels were quantified following addition of testcompound (agonism), as well as following addition of a submaximalconcentration of glutamate (potentiation).

For the determination of the effect of the test compound by itself(agonism) or by increasing the response to a submaximal concentration(e.g. 1 μM) of glutamate (potentiation), the resulting signal isdetermined by subtraction of the background fluorescence from themaximal fluorescent peak height of the respective response. In the FLIPRinstrument the compound is given to the cell and its fluorescenceresponse quantified by the FLIPR instrument (agonism). The concentrationat which the compound exerts half its maximal effect is named the‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced bythe test substance is normalized to the maximal effect exerted by 100 μMglutamate (set at 100%).

After addition of the test compound to the plate, a submaximalconcentration of glutamate (e.g. 1 μM glutamate) will be added. Apotentiator enhances the response of the receptor to glutamate. Theresponse to glutamate in the presence of test compound is quantified.The concentration at which the test compound is able to exert half itsmaximal potentiation effect to glutamate is named the ‘EC₅₀’. Themaximal response to the submaximal concentration of glutamate (e.g. 1micromolar glutamate) in the presence of test compound is normalized tothe maximal effect exerted by 100 micromolar glutamate (set at 100%).Least squares curve fitting with a four-parameter equation is thenapplied to the resulting dose-response curve to determine the resultingEC₅₀ values (Graph Pad Prism).

A control cell line, HEK293 cells expressing permanently rGLAST andGalpha16 was also plated to a multiwell plate for parallel testing toverify specificity of the test compound for mGlu2 receptor agonism orpotentiation.

The compounds of the invention can be further characterized bymeasurement of their efficacy and potency to inhibit forskolin-inducedcAMP levels in these cells on their own (agonism) or to potentiate theeffect of glutamate (potentiation). Cyclic AMP levels were quantifiedusing Alphascreen technology (PerkinElmer Life and Analytical Sciences,710 Bridgeport Avenue, Shelton, Conn. USA) as described by themanufacturer for determining the effects of Galphai coupled receptors.

The concentration at which a compound exerts half its maximal effect isnamed the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effectinduced by the test substance is normalized to the maximal effectexerted by 100 μM glutamate (100%). Least squares curve fitting with afour-parameter equation is then applied to the resulting dose-responsecurve to determine the resulting EC₅₀ values (Graph Pad Prism).

In particular, the compounds of the following examples had activity inpotentiating the mGlu2 receptor in the aforementioned assays, generallywith an EC₅₀ of not more than about 10 μM. Preferred compounds withinthe present invention had activity in potentiating the mGlu2 receptor inthe aforementioned assays with an EC₅₀ of less than 1 μM, in particularless than 0.5 μM, more preferably of at most 0.2 μM, of at most 0.1 μM.Such a result is indicative of the intrinsic activity of the compoundsin use as positive modulators of mGlu2 receptor activity.

As stated above, the compounds of the present invention are positivemodulators of metabotropic glutamate (mGluR) receptor function, inparticular they are positive modulators of mGlu2 receptors. Thus, thecompounds of the present invention can be used for treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with glutamatedysfunction, including one or more of the following conditions ordiseases: acute neurological and psychiatric disorders; such as cerebraldeficits subsequent to cardiac bypass surgery and grafting, stroke,cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia,cardiac arrest, hypoglycemic neuronal damage, dementia (includingAIDS-induced dementia), Alzheimer's disease, Huntington's Chorea,amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitivedisorders, idiopathic and drug-induced Parkinson's disease, muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, migraine (including migraine headache),urinary incontinence, disorders associated with substance tolerance,disorders associated with substance withdrawal (including substancessuch as opiates, nicotine, tobacco products, alcohol, benzodiazepines,cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety(including generalized anxiety disorder, panic disorder, and obsessivecompulsive disorder), mood disorders (including depression, mania,bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus,macular degeneration of the eye, emesis, brain edema, pain (includingacute and chronic pain states, severe pain, intractable pain,neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleepdisorders (including narcolepsy), attention deficit/hyperactivitydisorder, and conduct disorder.

Of the disorders above, the treatment of schizophrenia, anxiety,depression, substance-related disorders, migraine, and epilepsy are ofparticular importance.

Therefore, the present invention relates to a method for treating amedical disorder, selected from neurological and psychiatric disordersassociated with glutamate dysfunction, said method comprisingadministering an effective amount of at least one compound of thepresent invention to a subject in need thereof.

The compounds of the present invention frequently show an affinitytowards the serotonin 5HT_(2A) receptor. In particular the compounds ofthe present invention are antagonist of the serotonin 5HT_(2A) receptorand have binding constants Ki(5HT_(2A)) below 1 μM, in particular of atmost 0.5 μM, more preferably at most 250 nM or especially at most 100nM. Thus the compounds of the present invention are particularly usefulfor treating the above mentioned disorders, in particular psychiatricdisorders, such as schizophrenia, psychosis, cognitive disorders, drugabuse (i.e. disorders associated with substance tolerance, disordersassociated with substance withdrawal (including substances; such asopiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.), anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder). Theaffinity towards the 5HT2A receptor as well as the antagonistic actioncan be determined by routine screening techniques, a skilled person isfamiliar with (for reviews see e.g. D. E. Nichols, Hallocinogens, inPharmacology & Therapeutics 101 (2004) 131-181, J. A. Lieberman et al.Biol. Psychiatry 44 (1998) 1099-1117, S. Miyamoto et al., Mol.Psychiatry. 10 (2005), 79-104).

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom potentiation ofmetabotropic glutamate receptor activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. It is recognized thatone skilled in the art may affect the neurological and psychiatricdisorders by treating a patient presently afflicted with the disordersor by prophylactically treating a patient afflicted with the disorderswith an effective amount of the compound of the present invention. Asused herein, the terms “treatment” and “treating” refer to allprocesses; wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of the neurological andpsychiatric disorders described herein, but does not necessarilyindicate a total elimination of all disorder symptoms, as well as theprophylactic therapy of the mentioned conditions, particularly in apatient who is predisposed to such disease or disorder. The term“composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of and or “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individual in need of treatment.

A preferred embodiment of the present invention provides a method fortreating schizophrenia, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a N-oxide and/ora pharmaceutically acceptable salt thereof. In another preferredembodiment the present invention provides a method for preventing ortreating anxiety, comprising: administering to a patient in need thereofan effective amount of a compound of formula I, a tautomer and/or apharmaceutically acceptable salt thereof. Particularly preferred anxietydisorders are generalized anxiety disorder, panic disorder, andobsessive compulsive disorder.

In another preferred embodiment the present invention provides a methodfor treating substance-related disorders, comprising: administering to apatient in need thereof an effective amount of a compound of formula I,a tautomer and/or a pharmaceutically acceptable salt thereof. In anotherpreferred embodiment the present invention provides a method fortreating migraine, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. In yet anotherpreferred embodiment the present invention provides a method fortreating epilepsy, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof.

Of the neurological and psychiatric disorders associated with glutamatedysfunction which are treated according to the present invention, thetreatment of schizophrenia, anxiety, depression, migraine,substance-related disorders, especially substance dependence, substancetolerance, substance withdrawal, and epilepsy are particularlypreferred. Particularly preferred anxiety disorders are generalizedanxiety disorder, panic disorder, and obsessive compulsive disorder.

Thus, in a preferred embodiment the present invention provides a methodfor treating schizophrenia, comprising: administering to a patient inneed thereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. At present, thefourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) (1994, American Psychiatric Association, Washington,D.C.), provides a diagnostic tool including schizophrenia and otherpsychotic disorders. These include: disorders having psychotic symptomsas the defining feature. The term psychotic refers to delusions,prominent hallucinations, disorganized speech, disorganized or catatonicbehavior. The disorder includes: paranoid, disorganized, catatonic,undifferentiated, and residual schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition, substance-induced psychotic disorder, and psychotic disordernot otherwise specified. The skilled artisan will recognize that thereare alternative nomenclatures, nosologies, and classification systemsfor neurological and psychiatric disorders, and particularschizophrenia, and that these systems evolve with medical scientificprogress. Thus, the term “schizophrenia” is intended to include likedisorders that are described in other diagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating anxiety, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. At present, thefourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) (1994, American Psychiatric Association, Washington,D.C.), provides a diagnostic tool including anxiety and relateddisorders. These include: panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobia, socialphobia, obsessive-compulsive disorder, post-traumatic stress disorder,acute stress disorder, generalized anxiety disorder, anxiety disorderdue to a general medical condition, substance-induced anxiety disorderand anxiety disorder not otherwise specified. As used herein the term“anxiety” includes treatment of those anxiety disorders and relateddisorder as described in the DSM-IV. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies, and classificationsystems for neurological and psychiatric disorders, and particularanxiety, and that these systems evolve with medical scientific progress.Thus, the term “anxiety” is intended to include like disorders that aredescribed in other diagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating depression, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a N-oxide and/ora pharmaceutically acceptable salt thereof. At present, the fourthedition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV) (1994, American Psychiatric Association, Washington, D.C.),provides a diagnostic tool including depression and related disorders.Depressive disorders include, for example, single episodic or recurrentmajor depressive disorders, and dysthymic disorders, depressiveneurosis, and neurotic depression; melancholic depression includinganorexia, weight loss, insomnia and early morning waking, andpsychomotor retardation; atypical depression (or reactive depression)including increased appetite, hypersomnia, psychomotor agitation orirritability, anxiety and phobias; seasonal affective disorder; orbipolar disorders or manic depression, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder. As used herein the term“depression” includes treatment of those depression disorders andrelated disorder as described in the DSM-1V.

In another preferred embodiment, the present invention provides a methodfor treating substance-related disorders, especially substancedependence, substance abuse, substance tolerance, and substancewithdrawal, comprising: administering to a patient in need thereof aneffective amount of a compound of formula I, a tautomer and/or apharmaceutically acceptable salt thereof. At present, the fourth editionof the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)(1994, American Psychiatric Association, Washington, D.C.), provides adiagnostic tool including disorders related to taking a drug of abuse(including alcohol), to the side effects of a medication, and to toxinexposure. Substances include alcohol, amphetamine and similarly actingsympathomimetics, caffeine, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine (PCP) or similarly actingarylcyclohexylamines, and sedatives, hypnotics, or anxiolytics. Also,polysubstance dependence and other unknown substance-related disordersare included. The skilled artisan will recognize that there arealternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders, and particular substance-relateddisorders, and that these systems evolve with medical scientificprogress. Thus, the term “substance-related disorder” is intended toinclude like disorders that are described in other diagnostic sources.

In another preferred embodiment the present invention provides a methodfor treating migraine, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. In one of theavailable sources of diagnostic tools, Dorland's Medical Dictionary(23'rd Ed., 1982, W. B. Saunders Company, Philadelphia, Pa.), migraineis defined as a symptom complex of periodic headaches, usually temporaland unilateral, often with irritability, nausea, vomiting, constipationor diarrhea, and photophobia. As used herein the term “migraine includesthese periodic headaches, both temporal and unilateral, the associatedirritability, nausea, vomiting, constipation or diarrhea, photophobia,and other associated symptoms. The skilled artisan will recognize thatthere are alternative nomenclatures, nosologies, and classificationsystems for neurological and psychiatric disorders, including migraine,and that these systems evolve with medical scientific progress.

In another preferred embodiment the present invention provides a methodfor treating epilepsy, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. At present, there areseveral types and subtypes of seizures associated with epilepsy,including idiopathic, symptomatic, and cryptogenic. These epilepticseizures can be focal (partial) or generalized. They can also be simpleor complex. Epilepsy is described in the art, such as Epilepsy: Acomprehensive textbook. Ed. by Jerome Engel, Jr. and Timothy A. Pedley(Lippincott-Raven, Philadelphia, 1997). At present, the InternationalClassification of Diseases, Ninth Revision, (ICD-9) provides adiagnostic tool including epilepsy and related disorders. These include:generalized nonconvulsive epilepsy, generalized convulsive epilepsy,petit mal status epilepticus, grand mal status epilepticus, partialepilepsy with impairment of consciousness, partial epilepsy withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, other forms of epilepsy, epilepsy, unspecified, NOS. As usedherein the term “epilepsy” includes these all types and subtypes. Theskilled artisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, including epilepsy, and that these systems evolve withmedical scientific progress.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require potentiation of metabotropic glutamatereceptor activity an appropriate dosage level will generally be about0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0,20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day. When treating,preventing, controlling, ameliorating, or reducing the risk ofneurological and psychiatric disorders associated with glutamatedysfunction or other diseases for which compounds of the presentinvention are indicated, generally satisfactory results are obtainedwhen the compounds of the present invention are administered at a dailydosage of from about 0.1 milligram to about 100 milligram per kilogramof animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 milligramsto about 1000 milligrams, preferably from about 1 milligram to about 50milligrams, hi the case of a 70 kg adult human, the total daily dosewill generally be from about 7 milligrams to about 350 milligrams. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse. It will be understood, however, that the specific dose leveland frequency of dosage for any particular patient may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

The compounds according to the present invention are further useful in amethod for the prevention, treatment, control, amelioration, orreduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents, including an mGluR agonist.

The term “potentiated amount” refers to an amount of an mGluR agonist,that is, the dosage of agonist which is effective in treating theneurological and psychiatric disorders described herein whenadministered in combination with an effective amount of a compound ofthe present invention. A potentiated amount is expected to be less thanthe amount that is required to provide the same effect when the mGluRagonist is administered without an effective amount of a compound of thepresent invention.

A potentiated amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining a potentiated amount, the dose of an mGluRagonist to be administered in combination with a compound of formula I,a number of factors are considered by the attending diagnostician,including, but not limited to: the mGluR agonist selected to beadministered, including its potency and selectivity; the compound offormula Ito be coadministered; the species of mammal; its size, age, andgeneral health; the specific disorder involved; the degree ofinvolvement or the severity of the disorder; the response of theindividual patient; the modes of administration; the bioavailabilitycharacteristics of the preparations administered; the dose regimensselected; the use of other concomitant medication; and other relevantcircumstances.

A potentiated amount of an mGluR agonist to be administered incombination with an effective amount of a compound of formula I isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day and is expected to be lessthan the amount that is required to provided the same effect whenadministered without an effective amount of a compound of formula I.Preferred amounts of a co-administered mGlu agonist are able to bedetermined by one skilled in the art. The compounds of the presentinvention may be used in combination with one or more other drugs in thetreatment, prevention, control, amelioration, or reduction of risk ofdiseases or conditions for which compounds of Formula I or the otherdrugs may have utility, where the combination of the drugs together aresafer or more effective than either drug alone. Such other drug(s) maybe administered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of Formula I. When acompound of formula I is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchother drugs and the compound of formula I is preferred. However, thecombination therapy may also include therapies in which the compound offormula I and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the compounds ofthe present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof formula I. The above combinations include combinations of a compoundof the present invention not only with one other active compound, butalso with two or more other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered byconventional routes of administration, including parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), byinhalation spray, nasal, vaginal, rectal, sublingual, or topical routesof administration.

The compounds of the present invention may be formulated alone ortogether with further active compounds, in suitable dosage unitformulations containing conventional non-toxic pharmaceuticallyexcipients. Excipients can be solid, semisolid or liquid materials whichserve as vehicles, carriers or medium for the active compound. Suitableexcipients are listed in the specialist medicinal monographs. Inaddition, the formulations can comprise pharmaceutically acceptablecarriers or customary auxiliary substances, such as glidants; wettingagents; emulsifying and suspending agents; preservatives; antioxidants;antiirritants; chelating agents; coating auxiliaries; emulsionstabilizers; film formers; gel formers; odor masking agents; tastecorrigents; resin; hydrocolloids; solvents; solubilizers; neutralizingagents; diffusion accelerators; pigments; quaternary ammonium compounds;refatting and overfatting agents; raw materials for ointments, creams oroils; silicone derivatives; spreading auxiliaries; stabilizers;sterilants; suppository bases; tablet auxiliaries, such as binders,fillers, glidants, disintegrants or coatings; propellants; dryingagents; opacifiers; thickeners; waxes; plasticizers and white mineraloils. A formulation in this regard is based on specialist knowledge asdescribed, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe fürPharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliarysubstances for pharmacy, cosmetics and related fields], 4^(th) edition,Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops. Implanted release devices can also be usedfor administering inhibitors according to the invention. In addition, itis also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more excipients.

The following examples are intended for further illustration of thepresent invention.

PREPARATION EXAMPLES

Abbreviations used in the Examples that follow are: DCCdicyclohexylcarbodiimide; DCM dichloromethane; DMAN,N-dimethylacetamide; DMAP 4-dimethylaminopyridine; DMFdimethylformamide; DMSO dimethylsulfoxide; Et₂O diethyl ether; EtOAcethyl acetate; MeCN acetonitrile; MeOH methanol; RT room temperature;sat. saturated solutions; TFA trifluoroacetic acid; THF tetrahydrofuran;MP-CNBH₃ macroporous cyanoborohydride.

Preparative Example 1 ethyl 4-phenoxynicotinate

DCC (5.24 g, 25.4 mmol) was added in portions over 10 min to a solutionof 4-chloronicotinic acid (2.00 g, 12.7 mmol), ethanol (1.75 g, 38.1mmol) and DMAP (0.19 g, 1.52 mmol) in DMF (20 mL) at 0° C. Afterstiffing for 1 h the reaction mixture was allowed to warm to roomtemperature and stirred overnight. Water (100 mL) was added and thesolid formed was filtered off. The filtrate was extracted with DCM,washed with water, dried (MgSO₄) and the solvent was removed in vacuo.The crude ethyl 4-chloronicotinate (5.8 g) was dissolved in DMF (15 mL).Phenol (2.86 g, 30.4 mmol), copper powder (0.48 g, 7.59 mmol), copperiodide (0.72 g, 3.80 mmol) and K₂CO₃ (4.20 g, 30.4 mmol) were added. Thereaction mixture was heated to 80° C. for 3 h then allowed to cool toroom temperature and left overnight without stirring. The mixture waspoured into water and extracted with EtOAc. The combined organic layerswere washed with aqueous NaOH solution (1 M), water and dried overMgSO₄. Purification by flash chromatography (DCM/EtOAc, gradient 1-10%EtOAc) provided ethyl 4-phenoxynicotinate (1.59 g, 51% over 2 steps).ESI-MS [M+H]⁺=244.1.

Preparative Example 2 (4-(phenylamino)pyridin-3-yl)methanol

A mixture of 4-chloronicotinic acid (150 mg, 0.952 mmol) and aniline(177 mg, 1.90 mmol) in MeCN (2 mL) was stirred and heated in themicrowave (80° C., 300 W) for 1 h. The solid material was filtered offand the solvent was removed in vacuo. The crude 4-(phenylamino)nicotinicacid (202 mg) obtained was dissolved in THF (25 mL). After dropwiseaddition of LiAlH₄ (1 M solution in THF, 3.77 mL, 3.77 mmol) at 0° C.,the reaction mixture was stirred for 30 min, allowed to warm to roomtemperature and stirred overnight. The reaction was quenched with water(0.4 mL) at 0° C. and excess EtOAc was added. All solid material wasfiltered off and the solvent was removed in vacuo. Trituration with Et₂Oprovided (4-(phenylamino)pyridin-3-yl)methanol (115 mg, 60% over 2steps). ESI-MS [M+H]⁺=201.1.

Preparative Example 3 4-(benzylamino)nicotinic acid

A mixture of 4-chloronicotinic acid (300 mg, 1.90 mmol) and benzylamine(408 mg, 3.81 mmol) in MeCN (3 mL) was stirred and heated in themicrowave (80° C., 200 W) for 1 h. The solution obtained was partitionedbetween water and EtOAc. The precipitate formed was filtered off, washedwith water, EtOAc and dried in vacuo. 4-(benzylamino)nicotinic acid wasobtained as a colourless solid (147 mg, 34%). ESI-MS [M+H]⁺=229.1.

Preparative Example 4 4-phenylnicotinaldehyde

4-bromonicotinaldehyde (150 mg, 0.81 mmol), phenylboronic acid (98 mg,0.81 mmol) and tetrakis(triphenylphosphine) palladium(0) (46.6 mg, 0.05mmol) were mixed in dioxane (3.5 mL). Na₂CO₃ (2 M solution in water,0.81 mL, 1.63 mmol) was added and the reaction mixture was stirred andheated in the microwave (110° C., 150 W) for 30 min. After addition ofexcess water followed by extraction with EtOAc, the combined organiclayers were filtered (celite) and dried (MgSO₄). Purification by flashchromatography (heptane/EtOAc, gradient 5-40% EtOAc) provided4-phenylnicotinaldehyde (75 mg, 48%) as a dark yellow gum. ESI-MS[M+H]⁺=279.1.

The following intermediates were prepared in a manner analogous to thepreparation of 4-phenylnicotinaldehyde:

Preparative Example 5 4-(4-(trifluoromethyl)phenyl)nicotinaldehyde

Prepared by analogy to preparative example 4.

ESI-MS [M+H]⁺=252.0.

Preparative Example 6 4-(3-formylpyridin-4-yl)benzonitrile

Prepared by analogy to preparative example 4.

ESI-MS [M+H]⁺=209.1.

Preparative Example 7 (2-chloro-4-phenylpyridin-3-yl)methanol

Starting from (2-chloro-4-iodopyridin-3-yl)methanol. ESI-MS [M+H]⁺=269.9

Preparative Example 8 (2,6-dimethyl-4-phenylpyridin-3-yl)methanol

LiAlH₄ (1 M solution in THF, 8.93 mL, 8.93 mmol) was added dropwise to asolution of ethyl 2,6-dimethyl-4-phenylnicotinate (940 mg, 3.57 mmol) inTHF (38 mL) at 0° C. After stirring for 45 min, the reaction mixture wasallowed to warm to room temperature and the stirring was continued for75 min Water (0.2 mL) was added at 0° C. followed by NaOH (2 M, 0.2 mL)and water (0.2 mL). After the addition of excess EtOAc and filtration,the solvent was removed in vacuo providing(2,6-dimethyl-4-phenylpyridin-3-yl)methanol as a pale yellow gum (780mg, >99%). ESI-MS [M+H]⁺=214.1.

The following intermediates were prepared in a manner analogous to thepreparation of (2,6-dimethyl-4-phenylpyridin-3-yl)methanol:

Preparative Example 9 4-phenoxypyridin-3-yl)methanol

ESI-MS [M+H]+=202.1.

Preparative Example 10 4-(phenylamino)pyridin-3-yl)methanol

Starting from 4-(phenylamino)nicotinic acid using 4 eq of LiAlH₄ yieldedthe title compound. ESI-MS [M+H]⁺=201.1.

Preparative Example 11 (4-(benzylamino)pyridin-3-yl)methanol

Starting from 4-(benzylamino)nicotinic acid using 4 eq of LiAlH₄ yieldedthe title compound. ESI-MS [M+H]⁺=215.1.

Preparative Example 12 (2,6-dimethyl-4-phenylpyridin-3-yl)methylmethanesulfonate

NEt₃ (0.60 mL, 4.31 mmol) and methanesulphonyl chloride (0.20 mL, 2.59mmol) were added to a solution of(2,6-dimethyl-4-phenylpyridin-3-yl)methanol (460 mg, 2.16 mmol) in DCM(40 mL) at 0° C. After stirring for 40 min at 0° C. the reaction mixturewas diluted with DCM, washed with sat. aqueous NaHCO₃ solution, waterand dried (MgSO₄). Removal of the solvent provided crude(2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate which wasused without further purification (650 mg).

Preparative Example 13 4-phenoxynicotinaldehyde

MnO₂ (289 mg, 3.33 mmol) was added to a solution of(4-phenoxypyridin-3-yl)methanol (70 mg, 0.33 mmol) in THF (10 mL). Afterstiffing overnight the reaction mixture was filtered (celite). Removalof the solvent provided 4-phenoxynicotinaldehyde (70 mg, 95%). MS[M+H]⁺=200.1.

The following intermediates were prepared in a manner analogous to thepreparation of 4-phenoxynicotinaldehyde:

Preparative Example 14 4-(phenylamino)nicotinaldehyde

ESI-MS [M+H]⁺=199.1.

Preparative Example 15 4-(benzylamino)nicotinaldehyde

ESI-MS [M+H]⁺=213.1.

Example 12-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one

2-Butyl-5-hydroxyisoindolin-1-one (366 mg, 1.78 mmol), K₂CO₃ (493 mg,3.57 mmol) and KI (296 mg, 1.78 mmol) were added to a solution of(2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate (520 mg, 1.78mmol) in DMF (18 mL). After stirring overnight at room temperature (rt),water was added and the pH was adjusted to 13-14 using aqueous NaOH (1M). The reaction mixture was extracted with EtOAc, the combined organiclayers were washed with water, dried with MgSO₄ and the solvent wasremoved in vacuo. Purification by flash chromatography (DCM/MeOH,gradient 1-5% MeOH) provided2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one(140 mg, 19%). ESI-MS [M+H]⁺=401.2.

The following compounds of example 2-5 were prepared in a manneranalogous to the preparation of2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one:

Example 25-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)ethyl)isoindolin-1-one

ESI-MS [M+H]⁺=457.2.

Example 3 5-((4-phenoxypyridin-3-yl)methoxy)-2-propylisoindolin-1-one

ESI-MS [M+H]⁺=375.2.

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.95 (s, 1H); 8.70 (d, 1H); 7.60 (m,3H), 7.40 (t, 1H); 7.35 (s, 1H); 7.30 (d, 2H); 7.20 (d, 1H); 7.05 (d,1H); 5.45 (s, 2H); 4.40 (s, 2H); 3.45 (t, 2H); 1.60 (m, 2H); 0.85 (t,3H).

Example 42-butyl-5-((2-chloro-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one

ESI-MS [M+H]⁺=407.1.

Example 52-butyl-5-((2-chloro-4-iodopyridin-3-yl)methoxy)isoindolin-1-one

ESI-MS [M+H]⁺=457.0.

Example 65-(4-Phenyl-pyridin-3-ylmethoxy)-2-propyl-2,3-dihydro-isoindol-1-one

ESI-MS [M+H]⁺=359.20

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (s, 1H); 8.65 (d, 1H); 7.55 (d,1H); 7.45 (m, 6H); 7.10 (s, 1H); 7.00 (d, 1H); 5.10 (s, 2H); 4.35 (s,2H); 3.45 (t, 2H); 1.60 (m, 2H); 0.85 (t, 3H).

Example 75-(4-Phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydro-isoindol-1-one

ESI-MS [M+H]⁺=429.10

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (s, 1H); 8.65 (d, 1H); 7.60 (d,1H); 7.45 (m, 5H); 7.40 (d, 1H); 7.20 (s, 1H), 7.05 (d, 1H); 5.10 (s,2H); 4.45 (s, 2H); 4.30 (m, 2H); 3.80 (m, 2H).

Example 8[3-(1-oxo-2-propyl-2,3-dihydro-1H-isoindol-5-yloxymethyl)-pyridin-4-yl]-carbamicacid tert-butyl ester, trifluoroacetate

ESI-MS [M+H]⁺=398.20

Example 92-Butyl-5-(2,6-dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one

ESI-MS [M+H]⁺=401.20

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.55 (d, 1H); 7.40 (m, 5H); 7.15 (s,1H), 7.10 (s, 1H); 7.05 (d, 1H); 4.95 (s, 2H); 4.40 (s, 2H); 3.45 (t,2H); 2.60 (s, 3H); 2.50 (s, 3H); 1.55 (m, 2H); 1.30 (m, 2H); 0.85 (t,3H).

Example 105-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxyethyl)-2,3-dihydro-isoindol-1-one,trifluoroacetate

ESI-MS [M+H]⁺=457.20

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 7.75 (s, 1H); 7.60 (d, 1H); 7.50 (m,5H); 7.20 (s, 1H), 7.05 (d, 1H); 5.10 (s, 2H); 4.45 (s, 2H); 4.30 (t,2H); 3.80 (t, 2H); 2.80 (s, 3H); 2.70 (s, 3H).

Example 115-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-ethyl-2,3-dihydroisoindol-1-one

ESI-MS [M+H]⁺=373.20

¹H-NMR (400 MHz, d₆-DMSO): δ [ppm] 7.55 (d, 1H); 7.45 (m, 5H); 7.15 (s,1H), 7.10 (s, 1H); 7.05 (d, 1H); 4.95 (s, 2H); 4.40 (s, 2H); 3.50 (q,2H); 2.55 (s, 3H); 2.50 (s, 3H); 1.15 (t, 3H).

Example 125-[(4-methoxypyridin-3-yl)methoxy]-2-propyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS [M+H]⁺=313.10

Example 132-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one

5-Amino-2-butylisoindolin-1-one (63.1 mg, 0.309 mmol), K₂CO₃ (85 mg,0.618 mmol) and KI (51.3 mg, 0.309 mmol) were added to a solution of(2,6-dimethyl-4-phenylpyridin-3-yl)methyl methanesulfonate (90 mg, 0.309mmol) in DMF (6 mL). After stirring overnight, water was added, themixture was extracted with EtOAc, the combined organic layers werewashed with water and dried (MgSO₄). Purification by flashchromatography (DCM/MeOH, gradient 2-8% MeOH) provided2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one(51 mg, 40%). ESI-MS [M+H]⁺=400.2.

Example 142-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one

5-amino-2-butylisoindolin-1-one (35.0 mg, 0.17 mmol), ZnCl₂ (14.0 mg,0.10 mmol) and NaCNBH₄ (12.9 mg, 0.21 mmol) were consecutively added toa solution of 4-(trifluoromethyl)nicotinaldehyde (30.0 mg, 0.17 mmol) inMeOH (4 mL). After stirring overnight at room temperature excess waterwas added. The reaction mixture was extracted with EtOAc, the combinedorg. layers were washed with water, dried (MgSO₄) and the solvent wasremoved in vacuo. Purification by HPLC provided2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one*TFA(16.0 mg, 19%). ESI-MS [M+H]⁺=364.2.

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (m, 2H); 7.75 (d, 1H); 7.35 (d,1H), 6.65 (m, 2H); 4.55 (s, 2H); 4.25 (s, 2H); 3.40 (t, 2H); 1.50 (m,2H); 1.25 (m, 2H); 0.90 (t, 3H).

The following compounds were prepared in a manner analogous to thepreparation of2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one:

Example 15 2-butyl-5-((4-phenylpyridin-3-yl)methylamino)isoindolin-1-one

ESI-MS [M+H]⁺=372.2.

¹H-NMR (500 MHz, d₆-DMSO): δ [ppm] 8.80 (m, 2H); 7.70 (d, 1H); 7.60 (m,5H), 7.30 (d, 1H); 6.55 (d, 1H); 6.50 (s, 1H); 4.35 (s, 2H); 4.25 (s,2H); 3.40 (t, 2H); 1.50 (m, 2H); 1.25 (m, 2H); 0.90 (t, 3H).

Example 162-butyl-5-((4-phenoxypyridin-3-yl)methylamino)isoindolin-1-one

ESI-MS [M+H]⁺=388.2.

Example 172-butyl-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)methylamino)-isoindolin-1-one

ESI-MS [M+H]⁺=398.1.

Example 18 5-((4-aminopyridin-3-yl)methylamino)-2-butylisoindolin-1-one

Using 3 eq NaCNBH₄ and 0.9 eq ZnCl₂ for 8 days. ESI-MS [M+H]⁺=311.2.

Example 192-butyl-5-((4-(phenylamino)pyridin-3-yl)methylamino)isoindolin-1-one

Using 4.2 eq NaCNBH₄ and 1.2 eq ZnCl₂ for 8 days. ESI-MS [M+H]⁺=387.2.

Example 204-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)benzonitrile

ESI-MS [M+H+]=397.1.

Example 212-butyl-5-((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methylamino)-isoindolin-1-one

ESI-MS [M+H]⁺=440.2.

Example 222-butyl-5-[(pyridin-3-ylmethyl)amino]-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [2M+Na]⁺=613.30, [M+H⁺]=296.10

Example 237-chloro-2-cyclopropyl-5-{[(2,6-dimethyl-4-phenylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=418.20

Example 247-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-cyclopropyl-2,3-dihydro-1H-isoindol-1-one

¹H NMR (500 MHz, DMSO): δ [ppm] 8.73 (d, J=4.9 Hz, 1H), 7.90 (d, J=5.2Hz, 1H), 6.77 (m, 1H), 6.69 (d, J=4.9 Hz, 2H), 4.39 (d, J=3.4 Hz, 2H),4.24 (s, 2H), 2.82 (m, 1H), 0.68-0.83 (m, 4H).

Example 252-butyl-5-({[4-(morpholin-4-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one

¹H NMR (500 MHz, DMSO) δ[ppm] 8.39 (s, 1H), 8.31 (d, J=5.5, 1H), 7.32(d, J=8.3, 1H), 6.99 (d, J=5.5, 1H), 6.92 (t, J=5.8, 1H), 6.64 (d,J=8.3, 2H), 4.32-4.22 (m, 4H), 3.81-3.73 (m, 4H), 3.38 (t, 2H),3.05-2.97 (m, 4H), 1.56-1.46 (m, 2H), 1.25 (dt, J=7.3, 14.6, 2H), 0.88(t, J=7.4, 3H).

Example 262-butyl-5-({[4-(4-methylpiperazin-1-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one

¹H NMR (500 MHz, DMSO) δ[ppm] 8.38 (s, 1H), 8.28 (d, J=5.5 Hz, 1H), 7.33(d, J=8.8 Hz, 1H), 6.97 (d, J=5.5 Hz, 1H), 6.92 (t, J=5.8 Hz, 1H),6.61-6.67 (m, 2H), 4.23-4.31 (m, 3H), 3.33-3.41 (m, 3H), 3.02 (t, J=4.4Hz, 3H), 2.47-2.56 (m, 5H), 2.21-2.27 (m, 3H), 1.48-1.55 (m, 2H),1.21-1.29 (m, 2H), 0.89 (t, J=7.3 Hz, 3H)

Example 272-butyl-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=412.10;

¹H NMR (chloroform-d, 500 MHz): δ[ppm]=8.57 (d, J=4.9 Hz, 1H), 7.57 (d,J=5.2 Hz, 1H), 6.52 (d, 2H), 4.58 (s, 2H), 4.25 (s, 2H), 3.54 (t, J=7.3Hz, 2H), 3.12 (s br, 1H), 2.64 (s, 3H), 1.61 (t, J=7.3 Hz, 2H),1.35-1.40 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).

Example 282-butyl-7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: 434.10, [M]⁺=432.10;

¹H NMR (DMSO-d₆, 500 MHz): δ[ppm]=8.73 (d, J=5.2 Hz, 1H), 7.90 (d, J=4.9Hz, 1H), 6.74-6.78 (m, 2H), 6.69-6.71 (m, 1H), 4.41 (br. s., 2H), 4.31(s, 2H), 3.42 (t, J=7.0 Hz, 2H), 1.54 (quin, J=7.3 Hz, 2H), 1.25-1.31(m, 2H), 0.91 ppm (t, J=7.3 Hz, 3H)

Example 295-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H⁺]=438.10;

Example 305-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-propyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=398.10;

¹H NMR (DMSO-d₆, 500 MHz): δ [ppm]=8.71 (d, J=5.2 Hz, 1H), 7.87 (d,J=5.2 Hz, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 4.38 (s, 2H), 4.26 (s, 2H),3.37 (t, J=7.2 Hz, 2H), 2.50 (s, 3H), 1.54-1.59 (m, 2H), 0.86 ppm (t,J=7.5 Hz, 3H)

Example 315-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-ethyl-7-methyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=384.05;

¹H NMR (DMSO-d6, 500 MHz): δ [ppm]=8.71 (d, J=4.9 Hz, 1H), 7.88 (d,J=4.9 Hz, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 6.38 (br. s., 1H), 4.38 (br.s., 2H), 4.27 (s, 2H), 3.41-3.47 (m, 2H), 2.49 (br. s., 3H), 1.13 ppm(t, J=7.3 Hz, 3H)

Example 32 2-butyl-5-((5-phenylpyridin-3-yl)methylamino)isoindolin-1-one

ESI-MS: [M+H]⁺=372.2.

Example 332-butyl-5-{[(2-chloro-4-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=344.10

Example 345-{[(6-bromo-2-chloropyridin-3-yl)methyl]amino}-2-butyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=408.00

Example 352-butyl-5-{[(2,4-dichloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=364.05

Example 362-butyl-5-{[(6-chloro-2-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=360.10

Example 372-butyl-5-{[(2-chloro-6-methoxypyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=360.10

Example 382-butyl-5-{[(2-chloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=330.10

Example 395-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino-2-(2-methoxyethyl)-7-methyl-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=414.10

Example 402-butyl-5-{[(2,4-dichloro-6-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one

¹H NMR (DMSO-d₆, 500 MHz): δ[ppm]=7.63 (d, 1H), 7.18 (s, 1H), 6.75 (m,2H), 4.61 (s, 2H), 4.27 (s, 2H), 3.56 (r, 2H), 2.51 (s, 3H), 1.61(quint, 2H), 1.36 (quint, 2H), 0.94 (t, J=7.3 Hz, 3H).

Example 415-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=400.10

Example 425-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one

5-Amino-2-butylisoindolin-1-one (48.1 mg, 0.236 mmol) was added to asolution of 4-(benzylamino)nicotinaldehyde (50 mg, 0.236 mmol) in aceticacid (0.5 mL). Sodium triacetoxyborohydride (100 mg, 0.471 mmol) wasadded and the reaction mixture was stirred for 2 days. After theaddition of more triacetoxyborohydride (50 mg, 0.235 mmol) and stirringfor 6 h, water and sat aqueous NaHCO₃ solution were added. The mixturewas extracted with EtOAc, the combined org. layers washed with water anddried (MgSO₄). Purification by HPLC provided5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one (16mg, 13%). ESI-MS [M+H+]=401.2.

Example 43N-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)pivalamide

5-Amino-2-butylisoindolin-1-one (49.5 mg, 0.242 mmol) was added to asolution of N-(3-formylpyridin-4-yl)pivalamide (50 mg, 0.242 mmol) inacetic acid (1 mL). After stiffing for 5 days, water and sat aqueousNaHCO₃ solution were added. The mixture was extracted with EtOAc, thecombined organic layers were washed with water, dried over MgSO₄ and thesolvent was removed in vacuo. The residue obtained was dissolved in MeOH(3 mL) and NaBH₄ (18.3 mg, 0.485 mmol) was added. After stirringovernight, water and sat. aqueous NaHCO₃ solution were added. Extractionwith EtOAc, washing of the combined organic layers with water and dryingover MgSO₄ provided the crude product which was purified by HPLC (24 mg,19%). ESI-MS [M+H]⁺=395.2.

Example 442,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)-methyl)-4-phenylpyridine1-oxide

3-Chloroperbenzoic acid (19.3 mg, 0.112 mmol) was added to a solution of5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)-ethyl)isoindolin-1-one(40 mg, 0.074 mmol, 85% pure) in DCM. After stiffing overnight thereaction mixture was diluted with DCM, sat. aqueous NaHCO₃ solution wasadded. Extraction with DCM, washing of the combined organic layers withwater, drying over MgSO₄ followed by purification by HPLC provided2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)methyl)-4-phenylpyridine1-oxide (23 mg, 64%). ESI-MS [M+H]+=473.1.

The following compounds were prepared in an analogous manner.

Example 457-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-isoindol-1-oneExample 462-Butyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-oneCompound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=395.20

Example 477-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-propyl-2,3-dihydro-isoindol-1-oneCompound with Trifluoroacetic Acid Example 482-Ethyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-oneCompound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=367.20

Example 492-Butyl-5-[(2-methyl-4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-oneCompound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=395.20

Example 502-Butyl-5-[(4-[1,4]oxazepan-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-oneCompound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=395.20

Example 512-Butyl-5-({4-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-oneCompound with Trifluoroacetic Acid

ESI-MS: [M+H]⁺=397.20

Example 522-Butyl-5-({4-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one;compound with trifluoroacetic acid

ESI-MS: [M+H]⁺=397.20

Example 532-Butyl-5-({4-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one;compound with trifluoroacetic acid

ESI-MS: [M+H]⁺=383.20

Example 542-Butyl-5-(4-methoxy-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one

ESI-MS: [M+H]⁺=327.10

Example 552-Butyl-5-(4-morpholin-4-yl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one

ESI-MS: [M+H]⁺=382.20; [2M+Na]=675.30

Biological Tests:

I Generation of a HEK293 Cell Clones Permanently Expressing mGluReceptors and Functional Evaluation of the Cells

a) mGlu2 Receptor

For the purpose of the present study, a cell line permanently expressingthe human mGlu2 receptor, the rat glutamate transporter rGLAST and thealpha subunit of G16 was generated by transfection. Briefly, HEK293cells were seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶cells in DMEM with glutamax (Invitrogen, GIBCO # 21885-025), 10%dialyzed Fetal Calf Serum (Invitrogen, Gibco # 26400-044), and incubatedat 37° C. over night. The following day cells were transfected withLipofectamine (Invitrogen, Gibco #18324-012) as recommended by themanufacturer, using linearized pcDNA3.1 (V5/His)-hmGlu2 receptor (ScaI)and pcDNA3.1 Zeo-Ga16 IRES rGLAST (SspI). After transfection the cellswere selected in DMEM Glutamax Medium (Invitrogen, GIBCO # 21885-025),containing 10% dialyzed fetal calf serum (FCS; (Invitrogen, Gibco #26400-044), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 250μg/ml Zeozin. Single clones were isolated manually and further subclonedby serial dilution.

The function of the mGlu2 receptor was determined by evaluatingintracellular Ca²⁺ concentrations under standard conditions in afluorometric imaging plate reader (FLIPR, Molecular Devices, Union City,Calif. 94587, USA) by measuring the response of the cells to a testcompound. The FLIPR assay is a common functional assay to monitor nativeor recombinant Galphaq-coupled receptors, and native or recombinantreceptors normally linked to other G-protein signalling cascades, whichare coupled to calcium through co-expression of an alpha subunit of apromiscuous or chimeric G-protein. In the assay the increase ofintracellular calcium is measured through a calcium-dependentfluorescent dye (e.g. Fluo-4 AM) in the FLIPR instrument.

For selection of a suitable cell clone and also the subsequentmeasurements of the selected clone, 4×10⁴ cells/well were plated onpoly-D-lysine coated Biocoat-plates multiwell 96 in DMEM Glutamax (GIBCO# 21885-025)/10% dialyzed FCS over night. The following day, the mediumwas aspirated and exchanged for glutamate-free DMEM (Gibco # 21969-035),without FCS or glutamine, containing 50 μg/ml gentamycin (Gibco #15750). Cells were again incubated over night. Before the measurement,cells were loaded with 2 μM Fluo-4 AM (Molecular Probes, F14201; stocksolution 1 mM in DMSO) and 0.02% Pluronic F127 (Molecular Probes, P3000;stock solution 10% in DMSO) in DMEM medium (Gibco # 21969-035) for 45minutes at 37° C. in a final volume of 100 μl per well. Finally, theplates were washed in a BioTec cell washer with HBSS, containing 20 mMHEPES. The end-volume in each well was 100 μl. The plates weresubsequently measured in a fluorometric imaging plate reader (FLIPR,Molecular Devices, Union City, Calif. 94587, USA).

The compounds of the present invention were tested in theabove-described FLIPR assay using the selected cell clone. Increasedintracellular calcium levels were quantified following addition of testcompound (agonism), as well as following addition of a submaximalconcentration of 1 micromolar (1 μM) glutamate (potentiation).

For the determination of the effect of the test compound by itself(agonism) or by increasing the response to a submaximal concentration(e.g. 1 μM) of glutamate (potentiation), the resulting signal isdetermined by subtraction of the background fluorescence from themaximal fluorescent peak height of the respective response. In the FLIPRinstrument the compound is given to the cell and its fluorescenceresponse quantified by the FLIPR instrument (agonism). The concentrationat which the compound exerts half its maximal effect is named the‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced bythe test substance is normalized to the maximal effect exerted by 100 μMglutamate (set at 100%).

Ten minutes after addition of the test compound to the plate, 1 μMglutamate is added. A potentiator enhances the response of the receptorto glutamate. The response to glutamate in the presence of test compoundis quantified. The concentration at which the test compound is able toexert half its maximal potentiation effect to glutamate is named the‘EC₅₀’. The maximal response to 1 micromolar glutamate in the presenceof test compound is normalized to the maximal effect exerted by 100 μMglutamate (set at 100%). Least squares curve fitting with afour-parameter equation is then applied to the resulting dose-responsecurve to determine the resulting EC₅₀ values (Graph Pad Prism). Acontrol cell line, HEK293 cells expressing permanently rGLAST andGalpha16 was also plated at 4×10⁴ cells/well for parallel testing toverify specificity of the test compound for mGlu2 receptor agonism orpotentiation. The EC₅₀ values are given in table I.

Highly potent or key compounds were further characterized by measurementof their efficacy and potency to inhibit forskolin-induced cAMP levelsin these cells on their own (agonism) or to potentiate the effect ofglutamate (potentiation). Cyclic AMP levels were quantified usingAlphascreen technology (PerkinElmer Life and Analytical Sciences, 710Bridgeport Avenue, Shelton, Conn. USA) as described by the manufacturerfor determining the effects of Galphai coupled receptors. Theconcentration at which a compound exerts half its maximal effect isnamed the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effectinduced by the test substance is normalized to the maximal effectexerted by 100 μM glutamate (100%). Least squares curve fitting with afour-parameter equation is then applied to the resulting dose-responsecurve to determine the resulting EC₅₀ values (Graph Pad Prism).

The compounds of the following examples had activity in potentiating themGlu2 receptor in the aforementioned assays, generally with an EC₅₀ ofnot more than about 10 μM. Preferred compounds within the presentinvention had activity in potentiating the mGlu2 receptor in theaforementioned assays with an EC₅₀ of less than about 1 μM. Such aresult is indicative of the intrinsic activity of the compounds in useas potentiators of mGlu2 receptor activity.

TABLE I EXAMPLE EC₅₀ ¹⁾ 1 +++ 2 +++ 3 ++ 4 +++ 5 +++ 6 +++ 7 +++ 8 + 11+++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 19 ++ 20 +++ 21 +++ 22 + 23 +++24 +++ 25 ++ 26 + 33 ++ 34 ++ 35 +++ 36 ++ 37 ++ 38 + 39 ++ 42 + 43 ++44 +++ ¹⁾+++: EC₅₀ < 0.5 μM ++: 0.5 μM ≦ EC₅₀ ≦ 2 μM +: 2 μM < EC₅₀ < 10μM

b) mGlu3 Receptor

For the purpose of the present study, we generated by transfection acell line permanently expressing the human mGlu3 receptor, the ratglutamate transporter rGLAST and the alpha subunit of G16. Briefly,HEK293 cells were seeded in petri dishes (diameter 15 cm) at a densityof 2×10⁶ cells in DMEM with glutamax (Invitrogen, GIBCO # 21885-025),10% dialyzed Fetal Calf Serum (Invitrogen, Gibco # 26400-044), andincubated at 37° C. over night. The following day cells were transfectedwith Lipofectamine (Invitrogen, Gibco #18324-012) as recommended by themanufacturer, using linearized pcDNA3.1 (V5/His)-hmGlu3 receptor (ScaI)and pcDNA3.1 Zeo-Ga16 IRES rGLAST (SspI). After transfection the cellswere selected in DMEM Glutamax Medium (Invitrogen, GIBCO # 21885-025),containing 10% dialyzed fetal calf serum (FCS; (Invitrogen, Gibco #26400-044), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 250μg/ml Zeozin. Single clones were isolated manually and further subclonedby serial dilution. Function was tested with FLIPR as described above.

c) mGlu4 Receptor

For the purpose of the present study, we generated by transfection acell line permanently expressing human mGlu4 receptor, the rat glutamatetransporter rGLAST and the alpha subunit of G15. Briefly, HEK293 cellswere seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶ cellsin DMEM glutamax, 10% dialyzed FCS, and incubated at 37° C. over night.The following day cells were transfected with Lipofectamine (Invitrogen,Karlsruhe, Germany) as recommended by the manufacturer, using linearisedpcDNA3-hmGlu4 (SspI) and pcDNA3.1(+) Hygro-rGLAST IRES Gal5 (SspI).After transfection the cells were cultured in DMEM Glutamax Medium(Invitrogen), containing 10% dialyzed fetal calf serum (FCS;Invitrogen), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 150μg/ml Hygromycin, and single clones were isolated manually and subclonedby serial dilution. Function was tested with FLIPR as described above.

d) mGlu7 Receptor

For the purpose of the present study, we generated by transfection acell line permanently expressing human mGlu7a receptor, the ratglutamate transporter rGLAST and the alpha subunit of G15. Briefly,HEK293 cells were seeded in petri dishes (diameter 15 cm) at a densityof 2×10⁶ cells in DMEM glutamax, 10% dialyzed FCS, and incubated at 37°C. over night. The following day cells were transfected withLipofectamine (Invitrogen, Karlsruhe, Germany) as recommended by themanufacturer, using linearised pcDNA3(−)-hmGlu7a (SspI). Aftertransfection cells were cultured in DMEM Glutamax Medium (Invitrogen),containing 10% dialyzed fetal calf serum (FCS; Invitrogen),antibiotic/antimycotic (Invitrogen) and 800 μg/ml Geneticin (G418).Single clones were isolated manually, tested for reduction of cellularcAMP (alpha screen) and subcloned by FACS. Single cell clones wereretested for cAMP reduction, and transfected with pcDNA3.1 (+) HygrorGLAST IRES Gal5 (SspI). The transfection was done identical asdescribed above. Cells were selected in DMEM Glutamax, 10% dialyzed FCS,antibiotic/antimycotic, 800 μg/ml G418 and 150 μg/ml Hygromycin. Singleclones were isolated by serial dilution and tested by FLIPR as describedabove.

e) mGlu1 and 5 Receptors

For the purpose of the present study, we generated by transfection acell line permanently expressing human mGlu5a and the rat glutamatetransporter rGLAST. Briefly, cells were transfected with Lipofectamine(Invitrogen, Karlsruhe, Germany), using linearised pcDNA3-hmGlu5a (ScaI)and pIRES-rGlast (SspI). After transfection the cells were cultured inDMEM Glutamax Medium (Invitrogen), containing 10% dialyzed fetal calfserum (FCS; Invitrogen), antibiotic/antimycotic, 800 μg/ml Geneticin(G418) and 150 μg/ml Hygromycin, and single clones were isolatedmanually. Identically, a cell line expressing mGlu1a was generated.Functional clones were selected using intracellular Ca²⁺ measurementswith a fluorescence imaging plate reader (FLIPR) under standardconditions as described above.

1. Compounds of formula I

wherein X² is N or C—R² X³ is N or C—R³ X⁴ is N or C—R⁴ provided thatnone or one of X², X³ or X⁴ is N; Y¹ is N, C or C—R⁵ Y² is N, C or C—R⁶Y³ is N, C or C—R⁷ Y⁴ is N, C or C—R⁸ provided that only the moiety Y¹,Y², Y³ or Y⁴ to which Z is bound is C and further provided at most oneof Y¹, Y², Y³ or Y⁴ is N; Z is O, S, S(O), S(O)₂ or NR^(Z); R^(Z) ishydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl,C₁-C₄-alkyl, which is unsubstituted or carries one radical selected fromC₁-C₄-alkoxy and NR^(Z1)R^(Z2); where R^(Z1) and R^(Z2) areindependently of each other selected from hydrogen, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, orR^(Z1) and R^(Z2) together with the nitrogen to which they are attachedform a 5- or 6-membered N-bound saturated heterocycle, which, inaddition to the nitrogen atom, may comprise a further heteroatom,selected from O, S and N as ring member and which is unsubstituted orcarries 1, 2, 3 or 4 C₁-C₄-alkyl radicals; or R^(Z) is a radicalSO₂R^(Z3) or a radical S(O)₂NR^(Z4)R^(Z5); where R^(Z3) is C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, phenyl or benzyl, wherein the phenyl ring in thelast two mentioned radicals itself is unsubstituted or carries 1, 2, 3,4 or 5 identical or different radicals selected from halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, R^(Z4)and R^(Z5) have one of the meanings given for R^(Z1) and R^(Z2); Q isCH₂ or CH₂CH₂, where one or two of the hydrogen atoms in CH₂ or CH₂CH₂may be replaced by halogen, C₁-C₄-alkyl or C₁-C₄-haloalkyl; R¹ ishydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₄-haloalkoxy, C₃-C₈-cycloalkyl, a radical NR^(1a)R^(1b), C-bound 3-to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0or 1 heteroatoms, selected from O and S, as ring members, aryl,aryl-CH₂, aryloxy, hetaryl, hetaryloxy or hetaryl-CH₂, wherein theheterocyclyl, aryl and hetaryl rings ring in the last seven radicalsthemselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical ordifferent radicals R^(1c); R^(1a) is hydrogen, C₁-C₈-alkyl,C₁-C₈-haloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl,C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, benzyl, phenyl or 5- or6-membered hetaryl, wherein the phenyl and hetaryl rings in the lastthree radicals itself are unsubstituted or carry 1, 2, 3, 4 or 5identical or different radicals R^(1c); R^(1b) is hydrogen orC₁-C₄-alkyl; or NR^(1a)R^(1b) is a 3- to 10-membered mono- or bicyclicN-bound saturated heterocycle, which, in addition to the nitrogen atom,may comprise a further heteroatom, selected from O, S and N as ringmember and which is unsubstituted or carries 1, 2, 3 or 4 radicalsR^(1c); R^(1c) is selected from the group consisting of halogen, CN, OH,C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy; R², R³ and R⁴ are, independently of each other,selected from hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, phenyl,C₁-C₄-haloalkoxy, a radical (CH₂)_(n)NR′R″, where R′ and R″ have one ofthe meanings given for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or4, or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ringmembers, where the heterocyclyl itself is unsubstituted or carries 1, 2,3, 4 or 5 identical or different radicals R^(6c), where R^(6c) has oneof the meanings given for R^(1c); R⁵ is hydrogen, halogen, CN,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,C₁-C₄-haloalkoxy, (CH₂)_(n)NR′R″, where R′ and R″ have one of themeanings given for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4 orC-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogenatoms and 0 or 1 heteroatoms, selected from O and S, as ring members,where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or5 identical or different radicals R^(6c), where R^(6c) has one of themeanings given for R^(1c); R⁶, R⁷, R⁸ are, independently of each other,selected from hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,(CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given forR^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0or 1 heteroatoms, selected from O and S, as ring members, where theheterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(6c), where R^(6c) has one of themeanings given for R^(1c); R^(a) is C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl orC₁-C₆-alkyl, which is unsubstituted or carries one radical selected fromC₁-C₄-alkoxy, C₁-C₄-haloalkoxy and a radical NR^(a1)R^(a2), where R^(a1)and R^(a2) are independently of each other selected from hydrogen,C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl andC₁-C₄-alkoxy-C₁-C₄-alkyl, a radical NR^(a3)R^(a4) or a radicalN═C(R^(a5))R^(a6), where R^(a3) and R^(a5) are independently of eachother selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl;R^(a4) and R^(a6) are independently of each other selected fromhydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to10-membered, saturated heterocyclyl, 3- to 10-membered, saturatedheterocyclylmethyl, where heterocyclyl in the last two mentionedradicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected fromO and S, as ring members, aryl, aryl-CH₂, hetaryl and hetaryl-CH₂,wherein the heterocyclyl, aryl and hetaryl rings ring in the last sixradicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identicalor different radicals R^(ac), where R^(ac) has one of the meanings givenfor R^(1c); R^(b) is hydrogen, halogen or C₁-C₄-alkyl; and the N-oxidesand the pharmaceutically acceptable salts thereof.
 2. The compounds ofclaim 1, wherein R¹ is phenyl or phenoxy, wherein the phenyl ring inthese radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(1c).
 3. The compounds of claim 1,wherein R¹ is linear C₁-C₆-alkyl, branched C₃-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₄-haloalkoxy, halogen, C₃-C₆-cycloalkyl or C₁-C₆-haloalkyl.
 4. Thecompounds of claim 1, wherein R¹ is a radical NR^(1a)R^(1b) or C-bound3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atomsand 0 or 1 heteroatoms, selected from O and S, as ring members, wherethe heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(1c).
 5. The compounds of claim 1,wherein Z is O or NH.
 6. The compounds of claim 1, wherein X² is C—H. 7.The compounds of claim 1, wherein X² is N.
 8. The compounds of claim 1,wherein X³ is C—R³, wherein R³ is hydrogen, chlorine, methyl or methoxy.9. The compounds of claim 1, wherein X⁴ is C—R⁴, wherein R⁴ is hydrogen,chlorine, methyl or methoxy.
 10. The compounds of claim 6, wherein X² isC—H, X³ is C—R³ and X⁴ is C—R⁴, wherein R³ and R⁴ are, independentlyselected, from hydrogen, chlorine, methyl and methoxy.
 11. The compoundsof claim 7, wherein X² is N, X³ is C—R³ and X⁴ is C—R⁴, wherein R³ andR⁴ are, independently selected, from hydrogen, chlorine, methyl andmethoxy.
 12. The compounds of claim 1, wherein Y¹ is C—R⁵, Y² is C, Y³is C—R⁷ and Y⁴ is N or C—R⁸.
 13. The compounds of claim 1, wherein Y¹ isC—R⁵, Y³ is C, Y² is C—R⁶ and Y⁴ is N or C—R⁸.
 14. The compounds ofclaim 1, wherein R⁵ is hydrogen, chlorine, methyl or methoxy.
 15. Thecompounds of claim 1, wherein R⁶, R⁷ and R⁸, where present, arehydrogen.
 16. The compounds of claim 1, wherein R^(a) is C₃-C₆-alkyl orC₂-C₆-alkyl which carries one radical selected from C₁-C₄-alkoxy,C₁-C₄-haloalkoxy and the radical NR^(a1)R^(a2), where R^(a1) and R^(a2)are independently of each other selected from hydrogen, C₁-C₄-alkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl.17. The compounds of claim 1, wherein R^(a) is a radical NR^(a3)R^(a4),where R^(a3) is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl;R^(a4) is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,C-bound 3- to 7-membered, saturated heterocyclyl, 3- to 7-membered,saturated heterocyclylmethyl, where heterocyclyl in the last twomentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms,selected from O and S, as ring members, aryl, aryl-CH₂, hetaryl andhetaryl-CH₂, wherein the heterocyclyl, aryl and hetaryl rings ring inthe last six radicals themselves are unsubstituted or carry 1, 2, 3, 4or 5 identical or different radicals R^(ac), where R^(ac) has one of themeanings given for R^(1c).
 18. The compounds of claim 1, wherein R^(b)is hydrogen.
 19. The compounds of claim 1 of the formula Ia

wherein Z, Q, R¹, R³, R⁴, R⁵ and R^(a) are as defined above.
 20. Thecompounds of claim 1 of the formula Ib

wherein Z, Q, R¹, R³, R⁴, R⁵ and R^(a) are as defined above.
 21. Thecompound of claim 1 for use in therapy.
 22. Pharmaceutical compositionwhich comprises a carrier and a compound of claim
 1. 23. The compoundsof claim 1 for treating a medical disorder, selected from neurologicaland psychiatric disorders associated with glutamate dysfunction.
 24. Thecompounds of claim 1 for treating, controlling, ameliorating or reducingthe risk of anxiety, depression, migraine, schizophrenia, and epilepsyin a mammalian.
 25. The compounds of claim 1 for treating orameliorating the symptoms associated with substance-related disorders ina mammalian.
 26. A method for treating a medical disorder, selected fromneurological and psychiatric disorders associated with glutamatedysfunction, said method comprising administering an effective amount ofat least one compound of claim 1 to a subject in need thereof.